rs764196809

Positions:

chr17-75834092-ACTCC-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_199242.3(UNC13D):c.2346_2349del(p.Arg782SerfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,613,448 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

UNC13D
NM_199242.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.57

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-75834092-ACTCC-A is Pathogenic according to our data. Variant chr17-75834092-ACTCC-A is described in ClinVar as [Pathogenic]. Clinvar id is 420155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC13D	NM_199242.3 linkuse as main transcript	c.2346_2349del	p.Arg782SerfsTer12	frameshift_variant	24/32	ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9 linkuse as main transcript	c.2346_2349del	p.Arg782SerfsTer12	frameshift_variant	24/32	1	NM_199242.3	ENSP00000207549	P1	Q70J99-1
UNC13D	ENST00000412096.6 linkuse as main transcript	c.2346_2349del	p.Arg782SerfsTer12	frameshift_variant	24/33	2		ENSP00000388093		Q70J99-3
UNC13D	ENST00000699510.1 linkuse as main transcript	c.1212_1215del	p.Arg404SerfsTer12	frameshift_variant	12/20			ENSP00000514405
UNC13D	ENST00000591563.5 linkuse as main transcript	n.2616_2619del		non_coding_transcript_exon_variant	22/23	2

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000108

AC:

AN:

250908

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000212

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000158

AC:

231

AN:

1461458

Hom.:

AF XY:

0.000147

AC XY:

107

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000205

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151990

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.000110

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Aug 06, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change creates a premature translational stop signal (p.Arg782Serfs*12) in the UNC13D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UNC13D are known to be pathogenic (PMID: 14622600). This variant is present in population databases (rs764196809, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with familial hemophagocytic lymphohistiocytosis (PMID: 16278825, 18492689, 19484379, 20823128, 21248318, 26342526). ClinVar contains an entry for this variant (Variation ID: 420155). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 06, 2021	DNA sequence analysis of the UNC13D gene demonstrated a four base pair deletion in exon 24, c.2346_2349del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 12 amino acids downstream of the change, p.Arg782Serfs*12. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated UNC13D protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.02%in the non-Finnish European subpopulation (dbSNP rs764196809). This pathogenic sequence change has previously been described in an individuals with UNC13D-related hemophagocytic lymphohistiocytosis (PMID: 16278825, 32542393, 20823128, 17993578, 30295794). Collectively these evidences suggest that, the c.2346_2349del change is likely pathogenic, however functional studies have not been performed to prove this conclusively. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16278825, 16825436, 28973083, 20823128, 26342526, 30760465, 34426522, 31589614, 34677667, 32542393, 32500225, 17993578) -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -

Familial hemophagocytic lymphohistiocytosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 15, 2024

Variant summary: UNC13D c.2346_2349delGGAG (p.Arg782SerfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00011 in 250908 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in UNC13D causing Familial Hemophagocytic Lymphohistiocytosis (0.00011 vs 0.0027), allowing no conclusion about variant significance. c.2346_2349delGGAG has been reported in the literature in individuals affected with Familial Hemophagocytic Lymphohistiocytosis (e.g. Zur Stadt_2006). The following publication have been ascertained in the context of this evaluation (PMID: 16278825). ClinVar contains an entry for this variant (Variation ID: 420155). Based on the evidence outlined above, the variant was classified as pathogenic. -

Autoinflammatory syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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