rs8067076

chr17-75841061-A-Cchr17-75841061-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.570-60T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,603,944 control chromosomes in the GnomAD database, including 109,911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (20296 hom., cov: 28)
  • Exomes 𝑓: 0.34 (89615 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.408

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=-1.0).
• BP6: Variant 17-75841061-A-C is Benign according to our data. Variant chr17-75841061-A-C is described in ClinVar as [Benign]. Clinvar id is 1249408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3	c.570-60T>G		intron_variant		ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9	c.570-60T>G		intron_variant		1	NM_199242.3	P1

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70062 AN: 150622 Hom.: 20246 Cov.: 28

Gnomad AFR AF: 0.827

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.455

GnomAD4 exome AF: 0.340 AC: 493881 AN: 1453214 Hom.: 89615 Cov.: 30 AF XY: 0.340 AC XY: 245972 AN XY: 723416

Gnomad4 AFR exome AF: 0.847

Gnomad4 AMR exome AF: 0.261

Gnomad4 ASJ exome AF: 0.411

Gnomad4 EAS exome AF: 0.430

Gnomad4 SAS exome AF: 0.363

Gnomad4 FIN exome AF: 0.240

Gnomad4 NFE exome AF: 0.323

Gnomad4 OTH exome AF: 0.372

GnomAD4 genome AF: 0.465 AC: 70162 AN: 150730 Hom.: 20296 Cov.: 28 AF XY: 0.457 AC XY: 33591 AN XY: 73510

Gnomad4 AFR AF: 0.827

Gnomad4 AMR AF: 0.323

Gnomad4 ASJ AF: 0.422

Gnomad4 EAS AF: 0.417

Gnomad4 SAS AF: 0.351

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.329

Gnomad4 OTH AF: 0.460

Alfa AF: 0.349 Hom.: 9955

Bravo AF: 0.492

Asia WGS AF: 0.409 AC: 1422 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied by a panel of primary immunodeficiencies. Number of patients: 33. 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	-1.0
Cadd	Benign	2.1
Dann	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs8067076; hg19: chr17-73837142; COSMIC: COSV52883035; COSMIC: COSV52883035;