rs3744024

chr17-75835577-A-Gchr17-75835577-A-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.1728-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,608,438 control chromosomes in the GnomAD database, including 20,652 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (7615 hom., cov: 33)
  • Exomes 𝑓: 0.093 (13037 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.114

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=-0.93).
• BP6: Variant 17-75835577-A-G is Benign according to our data. Variant chr17-75835577-A-G is described in ClinVar as [Benign]. Clinvar id is 263217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.1728-48T>C		intron_variant		ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.1728-48T>C		intron_variant		1	NM_199242.3	P1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34519 AN: 152028 Hom.: 7596 Cov.: 33

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.0529

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.0683

Gnomad OTH AF: 0.205

GnomAD3 exomes AF: 0.139 AC: 33088 AN: 238450 Hom.: 4532 AF XY: 0.132 AC XY: 17168 AN XY: 129878

Gnomad AFR exome AF: 0.590

Gnomad AMR exome AF: 0.0925

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.337

Gnomad SAS exome AF: 0.154

Gnomad FIN exome AF: 0.0508

Gnomad NFE exome AF: 0.0693

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.0932 AC: 135673 AN: 1456292 Hom.: 13037 Cov.: 35 AF XY: 0.0941 AC XY: 68176 AN XY: 724146

Gnomad4 AFR exome AF: 0.594

Gnomad4 AMR exome AF: 0.0974

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.337

Gnomad4 SAS exome AF: 0.151

Gnomad4 FIN exome AF: 0.0533

Gnomad4 NFE exome AF: 0.0625

Gnomad4 OTH exome AF: 0.130

GnomAD4 genome AF: 0.227 AC: 34580 AN: 152146 Hom.: 7615 Cov.: 33 AF XY: 0.225 AC XY: 16739 AN XY: 74394

Gnomad4 AFR AF: 0.574

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.329

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.0529

Gnomad4 NFE AF: 0.0683

Gnomad4 OTH AF: 0.202

Alfa AF: 0.152 Hom.: 711

Bravo AF: 0.250

Asia WGS AF: 0.231 AC: 804 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	2.7
Dann	Benign	0.47
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: rs3744024; hg19: chr17-73831658; COSMIC: COSV52887762; COSMIC: COSV52887762;