dbSNP rs959968589: UNC13D:c.118-308C>T (chr17-75843827-G-A) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_199242.3(UNC13D):c.118-308C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,376,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

UNC13D
NM_199242.3 intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 0.359

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 Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-75843827-G-A is Pathogenic according to our data. Variant chr17-75843827-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 533095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75843827-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.118-308C>T		intron_variant	Intron 1 of 31	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.118-308C>T		intron_variant	Intron 1 of 31	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000194

AC:

237

AN:

1224488

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

114

AN XY:

590014

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000990

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000234

Gnomad4 OTH exome

AF:

0.0000200

GnomAD4 genome

AF:

0.000191

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000818

Hom.:

Bravo

AF:

0.000132

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3

Pathogenic:5Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Disruption of lymphocyte-specific enhancer [Meeths et al 2011]. Frequent cause of disease in persons of northern European background [Meeths et al 2011] & Koreans [Seo et al 2013] -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 1 of the UNC13D gene. It does not directly change the encoded amino acid sequence of the UNC13D protein. This variant is present in population databases (no rsID available, gnomAD 0.05%). This variant has been observed in individuals with familial hemophagocytic lymphohistiocytosis (FHL), and it has been described as a recurrent FHL-causing variant in Northern European and Korean populations (PMID: 21931115, 23180437, 24470399, 24935083, 25553300, 25573973). ClinVar contains an entry for this variant (Variation ID: 533095). Studies have shown that this variant alters UNC13D gene expression (PMID: 21931115, 24842371). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic. -

Dec 12, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.019%). Predicted Consequence/Location: Intron variant In silico tools do not predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.03 (<=0.1, moderate evidence for non-spliceogenicity)]. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23180437). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000533095 /PMID: 21931115). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2023

Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hemophagocytic lymphohistiocytosis

Pathogenic:1

May 26, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: UNC13D c.118-308C>T is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. Sequence analysis of patient samples confirmed these predictions, revealing correctly spliced products (Meeths_2011). The variant allele was found at a frequency of 0.00019 in 150968 control chromosomes (gnomAD v3.1.2). This frequency is not higher than expected for a pathogenic variant in UNC13D causing Familial Hemophagocytic Lymphohistiocytosis (0.00019 vs 0.0027), allowing no conclusion about variant significance. c.118-308C>T has been reported in the literature in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (e.g. Meeths_2011, Seo_2013). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant abolished an ELF1-binding site that is necessary for the recruitment of STAT4 and BRG1, diminishing active histone modifications at the locus and impaired UNC13D transcription in lymphocytes (Meeths_2011, Cichocki_2014). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Nov 16, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect as this variant disrupts an ELF1 transcription factor binding site and has a negative regulatory effect on transcription (PMID: 24842371); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 24935083, 29596912, 32582217, 25252047, 21931115, 25573973, 29665027, 24470399, 25553300, 32542393, 35773766, 33258288, 33365035, 32378134, 34170459, 23180437, 24842371, 34964741) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

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