rs74410877

chr17-75836303-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_199242.3(UNC13D):c.1389+36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,612,904 control chromosomes in the GnomAD database, including 10,422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (750 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9672 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.789

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-75836303-C-T is Benign according to our data. Variant chr17-75836303-C-T is described in ClinVar as [Benign]. Clinvar id is 263212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.1389+36G>A		intron_variant		ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.1389+36G>A		intron_variant		1	NM_199242.3	P1

Frequencies

GnomAD3 genomes AF: 0.0854 AC: 12995 AN: 152178 Hom.: 747 Cov.: 33

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.0963

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0888

Gnomad SAS AF: 0.0397

Gnomad FIN AF: 0.0760

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.106

GnomAD3 exomes AF: 0.0925 AC: 22906 AN: 247590 Hom.: 1213 AF XY: 0.0927 AC XY: 12444 AN XY: 134274

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.0848

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.0850

Gnomad SAS exome AF: 0.0421

Gnomad FIN exome AF: 0.0815

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.111 AC: 162552 AN: 1460608 Hom.: 9672 Cov.: 40 AF XY: 0.110 AC XY: 79774 AN XY: 726488

Gnomad4 AFR exome AF: 0.0183

Gnomad4 AMR exome AF: 0.0859

Gnomad4 ASJ exome AF: 0.132

Gnomad4 EAS exome AF: 0.0916

Gnomad4 SAS exome AF: 0.0431

Gnomad4 FIN exome AF: 0.0848

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.0854 AC: 13002 AN: 152296 Hom.: 750 Cov.: 33 AF XY: 0.0832 AC XY: 6197 AN XY: 74462

Gnomad4 AFR AF: 0.0219

Gnomad4 AMR AF: 0.0961

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.0894

Gnomad4 SAS AF: 0.0394

Gnomad4 FIN AF: 0.0760

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.110

Alfa AF: 0.107 Hom.: 192

Bravo AF: 0.0861

Asia WGS AF: 0.0780 AC: 269 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 18. Only high quality variants are reported. -

Familial hemophagocytic lymphohistiocytosis 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.98
Dann	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs74410877; hg19: chr17-73832384; COSMIC: COSV104392524; COSMIC: COSV104392524;