rs138760432

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_199242.3(UNC13D):c.2983G>C(p.Ala995Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,605,018 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 1 hom. )

Consequence

UNC13D
NM_199242.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:6

Conservation

PhyloP100: 2.64

Publications

8 publications found

Variant links:

Genes affected

UNC13D (HGNC:23147): (unc-13 homolog D) This gene encodes a protein that is a member of the UNC13 family, containing similar domain structure as other family members but lacking an N-terminal phorbol ester-binding C1 domain present in other Munc13 proteins. The protein appears to play a role in vesicle maturation during exocytosis and is involved in regulation of cytolytic granules secretion. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3, a genetically heterogeneous, rare autosomal recessive disorder. [provided by RefSeq, Jul 2008]

UNC13D Gene-Disease associations (from GenCC):

familial hemophagocytic lymphohistiocytosis 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
hereditary hemophagocytic lymphohistiocytosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

UNC13D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.033165008).

BP6

Variant 17-75828955-C-G is Benign according to our data. Variant chr17-75828955-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464457.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.001 (153/152378) while in subpopulation NFE AF = 0.00182 (124/68032). AF 95% confidence interval is 0.00156. There are 1 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.2983G>C	p.Ala995Pro	missense_variant	Exon 31 of 32	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9 link	c.2983G>C	p.Ala995Pro	missense_variant	Exon 31 of 32	1	NM_199242.3	ENSP00000207549.3

Frequencies

GnomAD3 genomes

AF:

0.00100

AC:

153

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00182

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000964

AC:

226

AN:

234442

AF XY:

0.000949

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000438

Gnomad ASJ exome

AF:

0.00266

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000646

Gnomad NFE exome

AF:

0.00169

Gnomad OTH exome

AF:

0.00102

GnomAD4 exome

AF:

0.00142

AC:

2063

AN:

1452640

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

988

AN XY:

723000

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33454

American (AMR)

AF:

0.000313

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00291

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.000176

AC:

AN:

45550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5288

European-Non Finnish (NFE)

AF:

0.00171

AC:

1896

AN:

1111534

Other (OTH)

AF:

0.000996

AC:

AN:

60230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

128

257

385

514

642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00100

AC:

153

AN:

152378

Hom.:

Cov.:

AF XY:

0.000966

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

41598

American (AMR)

AF:

0.000261

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00182

AC:

124

AN:

68032

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00139

Hom.:

Bravo

AF:

0.000971

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000909

AC:

110

EpiCase

AF:

0.00142

EpiControl

AF:

0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 23, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has been previously reported in cis with I848L in unrelated patients who had features of macrophage activation syndrome and autoimmune lymphoproliferative syndrome (Zhang et al., 2008; Arico et al., 2013; Kernan et al., 2018).; Transfection study of the I848L and A995P variants showed that these variants, both alone and in combination, decreased granule exocytosis when compared to wild type (Arico et al., 2013); This variant is associated with the following publications: (PMID: 33408077, 29977033, 18759271, 23840885, 29864493) -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

UNC13D: BP4 -

Familial hemophagocytic lymphohistiocytosis 3

Uncertain:2Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 28, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Aug 11, 2021

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The sequence change, c.2983G>C, in exon 31 results in an amino acid change, p.Ala995Pro. This sequence change has been previously described in one individual with autoimmune lymphoproliferative syndrome (PMID: 23840885), one individual with extreme hyperferritinemia (PMID: 29977033), and one individual with juvenile idiopathic arthritis (PMID: 33408077). This sequence change has been described in the gnomAD database with a low frequency of 0.27% in Ashkenazi Jewish subpopulation (dbSNP rs138760432). The p.Ala995Pro change affects a poorly conserved amino acid residue located in a domain of the UNC13D protein that is known to be functional. The p.Ala995Pro substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies show p.Ala995Pro is a loss-of-function variant (PMID: 23840885). Due to the lack of sufficient evidence, the clinical significance of the p.Ala995Pro change remains unknown at this time. -

UNC13D-related disorder

Uncertain:1

Jul 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The UNC13D c.2983G>C variant is predicted to result in the amino acid substitution p.Ala995Pro. This variant was reported in an individual with autoimmune lymphoproliferative syndrome who had inherited it as part of a haplotype that also contained another variant p.Ile848Leu from the unaffected mother (Aricò et al. 2013. PubMed ID: 23840885). Both variants have also been reported in an individual with septic shock and macrophage activation syndrome (Kernan et al. 2018. PubMed ID: 29977033) as well as in two individuals with polyarticular juvenile idiopathic arthritis (Meng et al. 2021. PubMed ID: 33408077). In vitro studies in a mastocytoma cell line showed that both variants, when expressed together as well as separately, resulted in defective secretory granule exocytosis; however, it is unclear how this finding relates to cells of the immune system in vivo (Aricò et al. 2013. PubMed ID: 23840885). This variant is reported in 0.27% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Autoinflammatory syndrome

Uncertain:1

Oct 02, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

9.1

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.061

T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.57

T;T

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.033

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-0.49

N;N

PhyloP100

2.6

PrimateAI

Benign

0.32

PROVEAN

Benign

0.39

N;N

REVEL

Benign

0.16

Sift

Benign

0.22

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.0010

B;.

Vest4

0.57

MVP

0.65

MPC

0.13

ClinPred

0.029

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.11

gMVP

0.45

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over