17-75843827-G-A

Position:

• chr17-75843827-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 0.359

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
UNC13D	NM_199242.3	c.118-308C>T		intron_variant		ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9	c.118-308C>T		intron_variant		1	NM_199242.3	ENSP00000207549.3

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152196 Hom.: 0 Cov.: 33

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.: 0 Cov.: 32 AF XY: 0.000193 AC XY: 114 AN XY: 590014

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: 29 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74344

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.: 0

Bravo AF: 0.000132

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Pathogenic:4 Other:1

not provided, no classification provided	literature only	GeneReviews	-	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] -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine	Jan 03, 2023	- -

Familial hemophagocytic lymphohistiocytosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 26, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 16, 2024

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	22
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

Other links and lift over

dbSNP: rs959968589; hg19: chr17-73839908;