rs118049905

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_199242.3(UNC13D):c.2896C>T(p.Arg966Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,580,010 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R966G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0037 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0060 ( 28 hom. )

Consequence

UNC13D
NM_199242.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.63

Publications

11 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009559631).

BP6

Variant 17-75830086-G-A is Benign according to our data. Variant chr17-75830086-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263237.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00373 (568/152280) while in subpopulation NFE AF = 0.00609 (414/68012). AF 95% confidence interval is 0.0056. There are 1 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.2896C>T	p.Arg966Trp	missense_variant	Exon 30 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.2896C>T	p.Arg966Trp	missense_variant	Exon 30 of 32	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.00373

AC:

568

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00442

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00609

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00441

AC:

852

AN:

193394

AF XY:

0.00448

show subpopulations

Gnomad AFR exome

AF:

0.00112

Gnomad AMR exome

AF:

0.00196

Gnomad ASJ exome

AF:

0.00426

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00486

Gnomad NFE exome

AF:

0.00763

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00599

AC:

8558

AN:

1427730

Hom.:

Cov.:

AF XY:

0.00582

AC XY:

4111

AN XY:

706932

show subpopulations

African (AFR)

AF:

0.000851

AC:

AN:

32918

American (AMR)

AF:

0.00192

AC:

AN:

39044

Ashkenazi Jewish (ASJ)

AF:

0.00485

AC:

123

AN:

25386

East Asian (EAS)

AF:

0.0000262

AC:

AN:

38152

South Asian (SAS)

AF:

0.000111

AC:

AN:

81382

European-Finnish (FIN)

AF:

0.00538

AC:

274

AN:

50960

Middle Eastern (MID)

AF:

0.000699

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00711

AC:

7786

AN:

1095000

Other (OTH)

AF:

0.00436

AC:

258

AN:

59168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

559

1119

1678

2238

2797

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00373

AC:

568

AN:

152280

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

251

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

41552

American (AMR)

AF:

0.00275

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00442

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00609

AC:

414

AN:

68012

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

102

136

170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00547

Hom.:

Bravo

AF:

0.00326

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00710

AC:

ExAC

AF:

0.00438

AC:

525

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

UNC13D: BS2 -

Dec 08, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in the heterozygous state without a second UNC13D variant in individuals with familial hemophagocytic lymphohistiocytosis in the literature (Zhang et al., 2014); these individuals also had a single heterozygous variant in the PRF1 gene suggesting possible digenic inheritance; Identified in the heterozygous state in patients with suspected bleeding disorders in published literature, although one of the patients also had a variant in the RUNX1 gene (Ferrari et al., 2018); This variant is associated with the following publications: (PMID: 24916509, 28399723) -

Familial hemophagocytic lymphohistiocytosis 3

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Benign:1

Jul 19, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

D;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0096

T;T

MetaSVM

Uncertain

0.040

MutationAssessor

Benign

1.9

L;L

PhyloP100

2.6

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.69

MVP

0.91

MPC

0.51

ClinPred

0.028

GERP RS

2.0

PromoterAI

0.0061

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.39

gMVP

0.57

Mutation Taster

=87/13

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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rs118049905

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