rs35628234

Positions:

• chr17-75830039-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_199242.3(UNC13D):​c.2943G>A​(p.Glu981=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0494 in 1,577,316 control chromosomes in the GnomAD database, including 2,567 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (558 hom., cov: 32)
  • Exomes 𝑓: 0.047 (2009 hom.)
• Consequence: UNC13D NM_199242.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.18

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 17-75830039-C-T is Benign according to our data. Variant chr17-75830039-C-T is described in ClinVar as [Benign]. Clinvar id is 263238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75830039-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.2943G>A	p.Glu981=	synonymous_variant	30/32	ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.2943G>A	p.Glu981=	synonymous_variant	30/32	1	NM_199242.3	P1

Frequencies

GnomAD3 genomes AF: 0.0713 AC: 10845 AN: 152156 Hom.: 553 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0430

Gnomad ASJ AF: 0.0634

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0835

Gnomad FIN AF: 0.0342

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0592

GnomAD3 exomes AF: 0.0516 AC: 9828 AN: 190444 Hom.: 359 AF XY: 0.0536 AC XY: 5443 AN XY: 101626

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.0232

Gnomad ASJ exome AF: 0.0588

Gnomad EAS exome AF: 0.0270

Gnomad SAS exome AF: 0.0924

Gnomad FIN exome AF: 0.0336

Gnomad NFE exome AF: 0.0429

Gnomad OTH exome AF: 0.0516

GnomAD4 exome AF: 0.0471 AC: 67125 AN: 1425042 Hom.: 2009 Cov.: 31 AF XY: 0.0485 AC XY: 34184 AN XY: 705126

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.0262

Gnomad4 ASJ exome AF: 0.0575

Gnomad4 EAS exome AF: 0.0375

Gnomad4 SAS exome AF: 0.0903

Gnomad4 FIN exome AF: 0.0357

Gnomad4 NFE exome AF: 0.0417

Gnomad4 OTH exome AF: 0.0531

GnomAD4 genome AF: 0.0713 AC: 10862 AN: 152274 Hom.: 558 Cov.: 32 AF XY: 0.0709 AC XY: 5275 AN XY: 74452

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.0430

Gnomad4 ASJ AF: 0.0634

Gnomad4 EAS AF: 0.0261

Gnomad4 SAS AF: 0.0838

Gnomad4 FIN AF: 0.0342

Gnomad4 NFE AF: 0.0454

Gnomad4 OTH AF: 0.0581

Alfa AF: 0.0599 Hom.: 156

Bravo AF: 0.0730

Asia WGS AF: 0.0570 AC: 200 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.0
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs35628234; hg19: chr17-73826120; COSMIC: COSV52884810; COSMIC: COSV52884810;