rs375724532

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_199242.3(UNC13D):c.2243C>T(p.Ala748Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000879 in 1,591,872 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A748T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000088 ( 1 hom. )

Consequence

UNC13D
NM_199242.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.63

Publications

2 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: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_199242.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0684858).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.2243C>T	p.Ala748Val	missense_variant	Exon 23 of 32	ENST00000207549.9	NP_954712.1	Q70J99-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9 link	c.2243C>T	p.Ala748Val	missense_variant	Exon 23 of 32	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000913

AC:

AN:

218964

AF XY:

0.0000748

show subpopulations

Gnomad AFR exome

AF:

0.0000714

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000993

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000882

AC:

127

AN:

1439532

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

716080

show subpopulations

African (AFR)

AF:

0.0000600

AC:

AN:

33306

American (AMR)

AF:

0.00

AC:

AN:

43840

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25924

East Asian (EAS)

AF:

0.000254

AC:

AN:

39344

South Asian (SAS)

AF:

0.0000235

AC:

AN:

85008

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4732

European-Non Finnish (NFE)

AF:

0.0000947

AC:

105

AN:

1109158

Other (OTH)

AF:

0.000134

AC:

AN:

59864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000853

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41584

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000965

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000869

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000833

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Apr 23, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: UNC13D c.2243C>T (p.Ala748Val) results in a non-conservative amino acid change located in the MUN domain (IPR010439) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 1585934 control chromosomes in the gnomAD database (v4.1 dataset), including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in UNC13D causing Familial Hemophagocytic Lymphohistiocytosis (0.0027), allowing no conclusion about variant significance. The variant, c.2243C>T, has been reported in the literature in heterozygous state individuals affected with (suspected) Familial Hemophagocytic Lymphohistiocytosis (e.g. Zhang_2014, McCreary_2019, Xinh_2021), however in at least one of these cases variants found in a different gene could possibly explain the phenotype (McCreary_2019). These reports do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated normal activity for the variant protein (Noori_2023). The following publications have been ascertained in the context of this evaluation (PMID: 31664448, 24916509, 31664448, 34339548). ClinVar contains an entry for this variant (Variation ID: 533089). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Mar 24, 2021

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the UNC13D gene demonstrated a sequence change, c.2243C>T, in exon 23 that results in an amino acid change, p.Ala748Val. This sequence change has been described in gnomAD with a low frequency of 0.053% (dbSNP rs375724532) in the East Asian sub-population. The p.Ala748Val change affects a moderately conserved amino acid residue located in a domain of the UNC13D protein that is not known to be functional. The p.Gln377Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD,REVEL). This sequence change has been reported in the heterozygous state in an individual with a clinical suspicion of hemophagocytic lymphohistiocytosis. This individual was also reported to have a heterozygous change in the PRF1 gene, suggesting a digenic mode of inheritance (PMID:24916509). Due to the lack of sufficient evidences, the clinical significance of the p.Gln377Arg change remains unknown at this time. -

Familial hemophagocytic lymphohistiocytosis 3

Uncertain:2

Jul 07, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 748 of the UNC13D protein (p.Ala748Val). This variant is present in population databases (rs375724532, gnomAD 0.06%). This missense change has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 24916509). ClinVar contains an entry for this variant (Variation ID: 533089). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt UNC13D protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Aug 07, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified as heterozygous without a second variant in an individual in the literature (Zhang et al., 2014) with familial hemophagocytic lymphohistiocytosis who also had a single heterozygous variant in the PRF1 gene suggesting possible digenic inheritance; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24916509) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

0.014

Eigen_PC

Benign

0.047

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.068

T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.90

L;L

PhyloP100

4.6

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.44

N;N

REVEL

Benign

0.26

Sift

Benign

1.0

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.95

P;P

Vest4

0.24

MVP

0.73

MPC

0.10

ClinPred

0.065

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.44

Mutation Taster

=88/12

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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rs375724532

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