rs372034111

chr17-75828860-G-Achr17-75828860-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6 BP7 BS1

The NM_199242.3(UNC13D):c.3078C>T(p.Pro1026=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,595,874 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1026P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: UNC13D NM_199242.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -7.09

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 Benign. Variant got -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-75828860-G-A is Benign according to our data. Variant chr17-75828860-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263239.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=-7.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000203 (293/1443550) while in subpopulation AFR AF= 0.00099 (33/33336). AF 95% confidence interval is 0.000724. There are 1 homozygotes in gnomad4_exome. There are 136 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.3078C>T	p.Pro1026=	synonymous_variant	31/32	ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.3078C>T	p.Pro1026=	synonymous_variant	31/32	1	NM_199242.3	P1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000287 AC: 61 AN: 212484 Hom.: 0 AF XY: 0.000282 AC XY: 33 AN XY: 116858

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000612

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00192

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.000741

GnomAD4 exome AF: 0.000203 AC: 293 AN: 1443550 Hom.: 1 Cov.: 31 AF XY: 0.000190 AC XY: 136 AN XY: 717272

Gnomad4 AFR exome AF: 0.000990

Gnomad4 AMR exome AF: 0.000190

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0000592

Gnomad4 FIN exome AF: 0.00194

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.000268

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000577 AC XY: 43 AN XY: 74482

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00282

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000560 Hom.: 0

Bravo AF: 0.000427

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

UNC13D: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.72
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs372034111; hg19: chr17-73824941;