rs3744010

chr17-75844162-G-A

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.117+59C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,589,986 control chromosomes in the GnomAD database, including 53,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8244 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44788 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.50

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=-0.81).
• BP6: Variant 17-75844162-G-A is Benign according to our data. Variant chr17-75844162-G-A is described in ClinVar as [Benign]. Clinvar id is 1166947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75844162-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.117+59C>T		intron_variant		ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.117+59C>T		intron_variant		1	NM_199242.3	P1

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46186 AN: 151932 Hom.: 8216 Cov.: 32

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.303

GnomAD4 exome AF: 0.243 AC: 349789 AN: 1437936 Hom.: 44788 Cov.: 29 AF XY: 0.242 AC XY: 173596 AN XY: 716068

Gnomad4 AFR exome AF: 0.501

Gnomad4 AMR exome AF: 0.202

Gnomad4 ASJ exome AF: 0.313

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.216

Gnomad4 FIN exome AF: 0.178

Gnomad4 NFE exome AF: 0.243

Gnomad4 OTH exome AF: 0.262

GnomAD4 genome AF: 0.304 AC: 46264 AN: 152050 Hom.: 8244 Cov.: 32 AF XY: 0.296 AC XY: 21978 AN XY: 74308

Gnomad4 AFR AF: 0.491

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.203

Gnomad4 FIN AF: 0.175

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.310

Alfa AF: 0.273 Hom.: 984

Bravo AF: 0.319

Asia WGS AF: 0.215 AC: 745 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported. -

Familial hemophagocytic lymphohistiocytosis 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.51
Dann	Benign	0.73
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: rs3744010; hg19: chr17-73840243; COSMIC: COSV52886233; COSMIC: COSV52886233;