17-75834107-C-T

Position:

chr17-75834107-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_199242.3(UNC13D):c.2335G>A(p.Val779Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,613,834 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.0035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 22 hom. )

Consequence

UNC13D
NM_199242.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 0.738

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 links:

UNC13D (HGNC:):

UNC13D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039931834).

BP6

Variant 17-75834107-C-T is Benign according to our data. Variant chr17-75834107-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403593.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}. Variant chr17-75834107-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00349 (531/152354) while in subpopulation NFE AF= 0.00569 (387/68028). AF 95% confidence interval is 0.00522. There are 0 homozygotes in gnomad4. There are 256 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC13D	NM_199242.3 linkuse as main transcript	c.2335G>A	p.Val779Met	missense_variant	24/32	ENST00000207549.9	NP_954712.1	Q70J99-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
UNC13D	ENST00000207549.9 linkuse as main transcript	c.2335G>A	p.Val779Met	missense_variant	24/32	1	NM_199242.3	ENSP00000207549.3	Q70J99-1
UNC13D	ENST00000412096.6 linkuse as main transcript	c.2335G>A	p.Val779Met	missense_variant	24/33	2		ENSP00000388093.1	Q70J99-3
UNC13D	ENST00000699510.1 linkuse as main transcript	c.1201G>A	p.Val401Met	missense_variant	12/20			ENSP00000514405.1	A0A8V8TNG5
UNC13D	ENST00000591563.5 linkuse as main transcript	n.2605G>A		non_coding_transcript_exon_variant	22/23	2

Frequencies

GnomAD3 genomes

AF:

0.00349

AC:

531

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00329

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00569

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00297

AC:

744

AN:

250866

Hom.:

AF XY:

0.00321

AC XY:

435

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.000740

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.00315

Gnomad NFE exome

AF:

0.00455

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00423

AC:

6179

AN:

1461480

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

2986

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00188

Gnomad4 ASJ exome

AF:

0.00241

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00146

Gnomad4 FIN exome

AF:

0.00332

Gnomad4 NFE exome

AF:

0.00490

Gnomad4 OTH exome

AF:

0.00421

GnomAD4 genome

AF:

0.00349

AC:

531

AN:

152354

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

256

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000793

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00329

Gnomad4 NFE

AF:

0.00569

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.00433

Hom.:

Bravo

AF:

0.00310

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00292

AC:

354

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00485

EpiControl

AF:

0.00462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	UNC13D: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with Haemophagocytic lymphohistiocytosis. This variant has been identified in the compound het state with a potential LOF in an individual with reduced levels of B-lymphocytes and IgGs (PMID 25502423). -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 01, 2021	- -

Familial hemophagocytic lymphohistiocytosis 3

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

Autoinflammatory syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 13, 2021

- -

UNC13D-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.15

N;N

REVEL

Benign

0.021

Sift

Benign

0.076

T;T

Sift4G

Benign

0.087

T;T

Polyphen

0.031

B;P

Vest4

0.14

MVP

0.65

MPC

0.10

ClinPred

0.0047

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.19

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over