17-75840081-C-G

Position:

chr17-75840081-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_199242.3(UNC13D):c.888G>C(p.Pro296Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,612,518 control chromosomes in the GnomAD database, including 107,485 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 19147 hom., cov: 33)

Exomes 𝑓: 0.34 ( 88338 hom. )

Consequence

UNC13D
NM_199242.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 0.608

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:

UNC13D (HGNC:):

UNC13D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 17-75840081-C-G is Benign according to our data. Variant chr17-75840081-C-G is described in ClinVar as [Benign]. Clinvar id is 263247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75840081-C-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.608 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.78 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.888G>C	p.Pro296Pro	synonymous_variant	11/32	ENST00000207549.9	NP_954712.1	Q70J99-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC13D	ENST00000207549.9 linkuse as main transcript	c.888G>C	p.Pro296Pro	synonymous_variant	11/32	1	NM_199242.3	ENSP00000207549.3		Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.454

AC:

68989

AN:

151982

Hom.:

19097

Cov.:

show subpopulations

Gnomad AFR

AF:

0.787

Gnomad AMI

AF:

0.279

Gnomad AMR

AF:

0.321

Gnomad ASJ

AF:

0.410

Gnomad EAS

AF:

0.418

Gnomad SAS

AF:

0.349

Gnomad FIN

AF:

0.238

Gnomad MID

AF:

0.453

Gnomad NFE

AF:

0.329

Gnomad OTH

AF:

0.450

GnomAD3 exomes

AF:

0.354

AC:

87671

AN:

247578

Hom.:

17621

AF XY:

0.352

AC XY:

47244

AN XY:

134354

show subpopulations

Gnomad AFR exome

AF:

0.803

Gnomad AMR exome

AF:

0.250

Gnomad ASJ exome

AF:

0.395

Gnomad EAS exome

AF:

0.419

Gnomad SAS exome

AF:

0.365

Gnomad FIN exome

AF:

0.235

Gnomad NFE exome

AF:

0.327

Gnomad OTH exome

AF:

0.353

GnomAD4 exome

AF:

0.338

AC:

493094

AN:

1460418

Hom.:

88338

Cov.:

AF XY:

0.338

AC XY:

245594

AN XY:

726504

show subpopulations

Gnomad4 AFR exome

AF:

0.807

Gnomad4 AMR exome

AF:

0.259

Gnomad4 ASJ exome

AF:

0.398

Gnomad4 EAS exome

AF:

0.429

Gnomad4 SAS exome

AF:

0.363

Gnomad4 FIN exome

AF:

0.239

Gnomad4 NFE exome

AF:

0.322

Gnomad4 OTH exome

AF:

0.368

GnomAD4 genome

AF:

0.454

AC:

69089

AN:

152100

Hom.:

19147

Cov.:

AF XY:

0.446

AC XY:

33137

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.788

Gnomad4 AMR

AF:

0.321

Gnomad4 ASJ

AF:

0.410

Gnomad4 EAS

AF:

0.418

Gnomad4 SAS

AF:

0.350

Gnomad4 FIN

AF:

0.238

Gnomad4 NFE

AF:

0.329

Gnomad4 OTH

AF:

0.454

Alfa

AF:

0.313

Hom.:

2330

Bravo

AF:

0.478

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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 43% of patients studied by a panel of primary immunodeficiencies. Number of patients: 41. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Familial hemophagocytic lymphohistiocytosis 3

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
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:2Other: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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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