Genetic Variant NM_199242.3:c.1389+36G>A (chr17-75836303-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.1389+36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,612,904 control chromosomes in the GnomAD database, including 10,422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.085 ( 750 hom., cov: 33)

Exomes 𝑓: 0.11 ( 9672 hom. )

Consequence

UNC13D
NM_199242.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.789

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=-0.91).

BP6

Variant 17-75836303-C-T is Benign according to our data. Variant chr17-75836303-C-T is described in ClinVar as [Benign]. Clinvar id is 263212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC13D	NM_199242.3 link	c.1389+36G>A		intron_variant	Intron 15 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.1389+36G>A		intron_variant	Intron 15 of 31	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.0854

AC:

12995

AN:

152178

Hom.:

747

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0220

Gnomad AMI

AF:

0.102

Gnomad AMR

AF:

0.0963

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.0888

Gnomad SAS

AF:

0.0397

Gnomad FIN

AF:

0.0760

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.123

Gnomad OTH

AF:

0.106

GnomAD3 exomes

AF:

0.0925

AC:

22906

AN:

247590

Hom.:

1213

AF XY:

0.0927

AC XY:

12444

AN XY:

134274

show subpopulations

Gnomad AFR exome

AF:

0.0179

Gnomad AMR exome

AF:

0.0848

Gnomad ASJ exome

AF:

0.127

Gnomad EAS exome

AF:

0.0850

Gnomad SAS exome

AF:

0.0421

Gnomad FIN exome

AF:

0.0815

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.107

GnomAD4 exome

AF:

0.111

AC:

162552

AN:

1460608

Hom.:

9672

Cov.:

AF XY:

0.110

AC XY:

79774

AN XY:

726488

show subpopulations

Gnomad4 AFR exome

AF:

0.0183

Gnomad4 AMR exome

AF:

0.0859

Gnomad4 ASJ exome

AF:

0.132

Gnomad4 EAS exome

AF:

0.0916

Gnomad4 SAS exome

AF:

0.0431

Gnomad4 FIN exome

AF:

0.0848

Gnomad4 NFE exome

AF:

0.122

Gnomad4 OTH exome

AF:

0.111

GnomAD4 genome

AF:

0.0854

AC:

13002

AN:

152296

Hom.:

750

Cov.:

AF XY:

0.0832

AC XY:

6197

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0219

Gnomad4 AMR

AF:

0.0961

Gnomad4 ASJ

AF:

0.123

Gnomad4 EAS

AF:

0.0894

Gnomad4 SAS

AF:

0.0394

Gnomad4 FIN

AF:

0.0760

Gnomad4 NFE

AF:

0.123

Gnomad4 OTH

AF:

0.110

Alfa

AF:

0.107

Hom.:

192

Bravo

AF:

0.0861

Asia WGS

AF:

0.0780

AC:

269

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2024

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 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 18. Only high quality variants are reported. -

Familial hemophagocytic lymphohistiocytosis 3

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.98

DANN

Benign

0.39

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