Genetic Variant UNC13D:c.154-19G>A (chr17-75843285-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_199242.3(UNC13D):c.154-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,602,580 control chromosomes in the GnomAD database, including 55,603 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 8145 hom., cov: 32)

Exomes 𝑓: 0.25 ( 47458 hom. )

Consequence

UNC13D
NM_199242.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.442

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=-0.78).

BP6

Variant 17-75843285-C-T is Benign according to our data. Variant chr17-75843285-C-T is described in ClinVar as [Benign]. Clinvar id is 263214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75843285-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.154-19G>A		intron_variant	Intron 2 of 31	ENST00000207549.9	NP_954712.1	Q70J99-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9 link	c.154-19G>A		intron_variant	Intron 2 of 31	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46174

AN:

151894

Hom.:

8116

Cov.:

show subpopulations

Gnomad AFR

AF:

0.480

Gnomad AMI

AF:

0.252

Gnomad AMR

AF:

0.228

Gnomad ASJ

AF:

0.291

Gnomad EAS

AF:

0.115

Gnomad SAS

AF:

0.207

Gnomad FIN

AF:

0.180

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.257

Gnomad OTH

AF:

0.301

GnomAD3 exomes

AF:

0.244

AC:

58503

AN:

239842

Hom.:

7857

AF XY:

0.242

AC XY:

31754

AN XY:

131134

show subpopulations

Gnomad AFR exome

AF:

0.492

Gnomad AMR exome

AF:

0.198

Gnomad ASJ exome

AF:

0.298

Gnomad EAS exome

AF:

0.111

Gnomad SAS exome

AF:

0.220

Gnomad FIN exome

AF:

0.187

Gnomad NFE exome

AF:

0.254

Gnomad OTH exome

AF:

0.252

GnomAD4 exome

AF:

0.251

AC:

363713

AN:

1450568

Hom.:

47458

Cov.:

AF XY:

0.249

AC XY:

180061

AN XY:

721984

show subpopulations

Gnomad4 AFR exome

AF:

0.486

Gnomad4 AMR exome

AF:

0.202

Gnomad4 ASJ exome

AF:

0.299

Gnomad4 EAS exome

AF:

0.108

Gnomad4 SAS exome

AF:

0.220

Gnomad4 FIN exome

AF:

0.185

Gnomad4 NFE exome

AF:

0.254

Gnomad4 OTH exome

AF:

0.260

GnomAD4 genome

AF:

0.304

AC:

46247

AN:

152012

Hom.:

8145

Cov.:

AF XY:

0.295

AC XY:

21941

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.480

Gnomad4 AMR

AF:

0.227

Gnomad4 ASJ

AF:

0.291

Gnomad4 EAS

AF:

0.116

Gnomad4 SAS

AF:

0.208

Gnomad4 FIN

AF:

0.180

Gnomad4 NFE

AF:

0.257

Gnomad4 OTH

AF:

0.308

Alfa

AF:

0.206

Hom.:

651

Bravo

AF:

0.318

Asia WGS

AF:

0.214

AC:

745

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial hemophagocytic lymphohistiocytosis 3

Benign:3

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.91

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

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