rs3744007

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_199242.3(UNC13D):c.279C>T(p.Pro93=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,609,490 control chromosomes in the GnomAD database, including 2,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 343 hom., cov: 32)

Exomes 𝑓: 0.031 ( 2368 hom. )

Consequence

UNC13D
NM_199242.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.26

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 17-75843056-G-A is Benign according to our data. Variant chr17-75843056-G-A is described in ClinVar as [Benign]. Clinvar id is 263235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75843056-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.26 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.26 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.279C>T	p.Pro93=	synonymous_variant	4/32	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.279C>T	p.Pro93=	synonymous_variant	4/32	1	NM_199242.3	ENSP00000207549	P1	Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.0450

AC:

6843

AN:

151958

Hom.:

343

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0642

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0338

Gnomad ASJ

AF:

0.0755

Gnomad EAS

AF:

0.273

Gnomad SAS

AF:

0.0519

Gnomad FIN

AF:

0.0184

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0204

Gnomad OTH

AF:

0.0555

GnomAD3 exomes

AF:

0.0495

AC:

12144

AN:

245370

Hom.:

885

AF XY:

0.0487

AC XY:

6526

AN XY:

133878

show subpopulations

Gnomad AFR exome

AF:

0.0629

Gnomad AMR exome

AF:

0.0234

Gnomad ASJ exome

AF:

0.0665

Gnomad EAS exome

AF:

0.282

Gnomad SAS exome

AF:

0.0444

Gnomad FIN exome

AF:

0.0162

Gnomad NFE exome

AF:

0.0238

Gnomad OTH exome

AF:

0.0417

GnomAD4 exome

AF:

0.0312

AC:

45465

AN:

1457414

Hom.:

2368

Cov.:

AF XY:

0.0319

AC XY:

23137

AN XY:

725090

show subpopulations

Gnomad4 AFR exome

AF:

0.0670

Gnomad4 AMR exome

AF:

0.0236

Gnomad4 ASJ exome

AF:

0.0660

Gnomad4 EAS exome

AF:

0.283

Gnomad4 SAS exome

AF:

0.0439

Gnomad4 FIN exome

AF:

0.0169

Gnomad4 NFE exome

AF:

0.0190

Gnomad4 OTH exome

AF:

0.0447

GnomAD4 genome

AF:

0.0449

AC:

6834

AN:

152076

Hom.:

343

Cov.:

AF XY:

0.0465

AC XY:

3453

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0640

Gnomad4 AMR

AF:

0.0338

Gnomad4 ASJ

AF:

0.0755

Gnomad4 EAS

AF:

0.272

Gnomad4 SAS

AF:

0.0520

Gnomad4 FIN

AF:

0.0184

Gnomad4 NFE

AF:

0.0204

Gnomad4 OTH

AF:

0.0549

Alfa

AF:

0.0231

Hom.:

Bravo

AF:

0.0495

Asia WGS

AF:

0.128

AC:

443

AN:

3478

EpiCase

AF:

0.0274

EpiControl

AF:

0.0309

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3

Benign:3

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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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

-0.85

CADD

Benign

0.057

DANN

Benign

0.70

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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