rs754621494

Positions:

• chr17-75835410-T-C
• chr17-75835410-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_199242.3(UNC13D):​c.1847A>G​(p.Glu616Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000411 in 1,459,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: UNC13D NM_199242.3 missense, splice_region
• Scores: Splicing: ADA: 0.9973
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.23

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-75835410-T-C is Pathogenic according to our data. Variant chr17-75835410-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 445606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.1847A>G	p.Glu616Gly	missense_variant, splice_region_variant	20/32	ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.1847A>G	p.Glu616Gly	missense_variant, splice_region_variant	20/32	1	NM_199242.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459368 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 725906

Gnomad4 AFR exome AF: 0.00

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 28, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 616 of the UNC13D protein (p.Glu616Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 16825436, 21248318, 29312353). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 445606). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Familial hemophagocytic lymphohistiocytosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 30, 2021

Variant summary: UNC13D c.1847A>G (p.Glu616Gly) results in a non-conservative amino acid change located in the Munc13 homology 1 domain (IPR014770) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant also alters a conserved nucleotide located in the exonic-splice region two nucleotides from the end of exon 20. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing of exon 20, with causing a deletion of nine amino acids, which remained in frame (Santoro_2006). The variant was absent in 244878 control chromosomes. c.1847A>G has been reported in the literature in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (example, Santoro_2006, Sieni_2011, Shibata_2017, Giardino_2017). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

May 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.66	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.11
Sift	Benign	0.17	T;T
Sift4G	Uncertain	0.016	D;D
Polyphen		0.12	B;B
Vest4		0.30
MutPred		0.37		Loss of solvent accessibility (P = 0.0299);Loss of solvent accessibility (P = 0.0299);
MVP		0.64
MPC		0.13
ClinPred		0.38	T
GERP RS		-0.47
Varity_R		0.080
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.42		Position offset: 26
DS_DL_spliceai		0.54		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs754621494; hg19: chr17-73831491;