rs35037984

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_199242.3(UNC13D):c.2782C>T(p.Arg928Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,588,302 control chromosomes in the GnomAD database, including 390 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R928H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 36 hom., cov: 33)

Exomes 𝑓: 0.021 ( 354 hom. )

Consequence

UNC13D
NM_199242.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.92

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008826911).

BP6

Variant 17-75830410-G-A is Benign according to our data. Variant chr17-75830410-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75830410-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0173 (2628/152264) while in subpopulation AMR AF= 0.0256 (392/15296). AF 95% confidence interval is 0.0235. There are 36 homozygotes in gnomad4. There are 1266 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC13D	NM_199242.3 linkuse as main transcript	c.2782C>T	p.Arg928Cys	missense_variant	29/32	ENST00000207549.9	NP_954712.1	Q70J99-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9 linkuse as main transcript	c.2782C>T	p.Arg928Cys	missense_variant	29/32	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2629

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00333

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0257

Gnomad ASJ

AF:

0.0185

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0196

Gnomad FIN

AF:

0.0185

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0244

Gnomad OTH

AF:

0.0225

GnomAD3 exomes

AF:

0.0190

AC:

3894

AN:

205488

Hom.:

AF XY:

0.0198

AC XY:

2189

AN XY:

110626

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.0123

Gnomad ASJ exome

AF:

0.0170

Gnomad EAS exome

AF:

0.0000639

Gnomad SAS exome

AF:

0.0221

Gnomad FIN exome

AF:

0.0223

Gnomad NFE exome

AF:

0.0252

Gnomad OTH exome

AF:

0.0214

GnomAD4 exome

AF:

0.0205

AC:

29491

AN:

1436038

Hom.:

354

Cov.:

AF XY:

0.0208

AC XY:

14828

AN XY:

712082

show subpopulations

Gnomad4 AFR exome

AF:

0.00332

Gnomad4 AMR exome

AF:

0.0127

Gnomad4 ASJ exome

AF:

0.0160

Gnomad4 EAS exome

AF:

0.0000774

Gnomad4 SAS exome

AF:

0.0224

Gnomad4 FIN exome

AF:

0.0209

Gnomad4 NFE exome

AF:

0.0221

Gnomad4 OTH exome

AF:

0.0187

GnomAD4 genome

AF:

0.0173

AC:

2628

AN:

152264

Hom.:

Cov.:

AF XY:

0.0170

AC XY:

1266

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00332

Gnomad4 AMR

AF:

0.0256

Gnomad4 ASJ

AF:

0.0185

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0201

Gnomad4 FIN

AF:

0.0185

Gnomad4 NFE

AF:

0.0244

Gnomad4 OTH

AF:

0.0222

Alfa

AF:

0.0222

Hom.:

Bravo

AF:

0.0157

TwinsUK

AF:

0.0235

AC:

ALSPAC

AF:

0.0205

AC:

ESP6500AA

AF:

0.00296

AC:

ESP6500EA

AF:

0.0225

AC:

193

ExAC

AF:

0.0165

AC:

1984

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2023	See Variant Classification Assertion Criteria. -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, 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: Not present in FAST (due to DM? classification). ExAC: 4.7% (56/1194) Finnish -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Familial hemophagocytic lymphohistiocytosis 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.86

D;D

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.6

L;L

PrimateAI

Benign

0.24

PROVEAN

Benign

1.6

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.13

T;T

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.41

B;.

Vest4

0.20

MPC

0.17

ClinPred

0.0075

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Varity_R

0.11

gMVP

0.45

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