17-75834915-C-T

Position:

chr17-75834915-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000207549.9(UNC13D):c.1992+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,613,612 control chromosomes in the GnomAD database, including 38,465 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 2989 hom., cov: 32)

Exomes 𝑓: 0.22 ( 35476 hom. )

Consequence

UNC13D
ENST00000207549.9 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.9297

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -0.241

Variant links:

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]

UNC13D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 17-75834915-C-T is Benign according to our data. Variant chr17-75834915-C-T is described in ClinVar as [Benign]. Clinvar id is 263222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75834915-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC13D	NM_199242.3 linkuse as main transcript	c.1992+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000207549.9	NP_954712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9 linkuse as main transcript	c.1992+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_199242.3	ENSP00000207549	P1	Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.193

AC:

29309

AN:

151854

Hom.:

2980

Cov.:

show subpopulations

Gnomad AFR

AF:

0.155

Gnomad AMI

AF:

0.237

Gnomad AMR

AF:

0.161

Gnomad ASJ

AF:

0.204

Gnomad EAS

AF:

0.0925

Gnomad SAS

AF:

0.169

Gnomad FIN

AF:

0.179

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.234

Gnomad OTH

AF:

0.197

GnomAD3 exomes

AF:

0.189

AC:

47583

AN:

251306

Hom.:

4826

AF XY:

0.193

AC XY:

26286

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.148

Gnomad AMR exome

AF:

0.134

Gnomad ASJ exome

AF:

0.210

Gnomad EAS exome

AF:

0.0860

Gnomad SAS exome

AF:

0.184

Gnomad FIN exome

AF:

0.177

Gnomad NFE exome

AF:

0.230

Gnomad OTH exome

AF:

0.205

GnomAD4 exome

AF:

0.217

AC:

317337

AN:

1461640

Hom.:

35476

Cov.:

AF XY:

0.217

AC XY:

157554

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.148

Gnomad4 AMR exome

AF:

0.138

Gnomad4 ASJ exome

AF:

0.217

Gnomad4 EAS exome

AF:

0.0933

Gnomad4 SAS exome

AF:

0.185

Gnomad4 FIN exome

AF:

0.178

Gnomad4 NFE exome

AF:

0.232

Gnomad4 OTH exome

AF:

0.211

GnomAD4 genome

AF:

0.193

AC:

29331

AN:

151972

Hom.:

2989

Cov.:

AF XY:

0.188

AC XY:

13994

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.154

Gnomad4 AMR

AF:

0.161

Gnomad4 ASJ

AF:

0.204

Gnomad4 EAS

AF:

0.0931

Gnomad4 SAS

AF:

0.169

Gnomad4 FIN

AF:

0.179

Gnomad4 NFE

AF:

0.234

Gnomad4 OTH

AF:

0.204

Alfa

AF:

0.227

Hom.:

6795

Bravo

AF:

0.191

Asia WGS

AF:

0.164

AC:

568

AN:

3478

EpiCase

AF:

0.240

EpiControl

AF:

0.240

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
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 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 30. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Familial hemophagocytic lymphohistiocytosis 3

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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 provided

Benign:1Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.3

DANN

Benign

0.51

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.93

dbscSNV1_RF

Benign

0.21

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.25

Position offset: 15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over