rs140758914

Variant summary

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

The NM_199242.3(UNC13D):c.951+13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,613,498 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 51 hom., cov: 32)

Exomes 𝑓: 0.018 ( 456 hom. )

Consequence

UNC13D
NM_199242.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.323

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=-0.83).

BP6

Variant 17-75840005-A-C is Benign according to our data. Variant chr17-75840005-A-C is described in ClinVar as [Benign]. Clinvar id is 263248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75840005-A-C is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC13D	NM_199242.3 linkuse as main transcript	c.951+13T>G		intron_variant		ENST00000207549.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC13D	ENST00000207549.9 linkuse as main transcript	c.951+13T>G		intron_variant		1	NM_199242.3	P1	Q70J99-1

Frequencies

GnomAD3 genomes

AF:

0.0170

AC:

2582

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0196

Gnomad ASJ

AF:

0.0744

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0273

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0180

Gnomad OTH

AF:

0.0325

GnomAD3 exomes

AF:

0.0187

AC:

4654

AN:

249368

Hom.:

AF XY:

0.0202

AC XY:

2739

AN XY:

135270

show subpopulations

Gnomad AFR exome

AF:

0.0128

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.0637

Gnomad EAS exome

AF:

0.000273

Gnomad SAS exome

AF:

0.0251

Gnomad FIN exome

AF:

0.00136

Gnomad NFE exome

AF:

0.0202

Gnomad OTH exome

AF:

0.0263

GnomAD4 exome

AF:

0.0183

AC:

26705

AN:

1461150

Hom.:

456

Cov.:

AF XY:

0.0190

AC XY:

13802

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.0159

Gnomad4 AMR exome

AF:

0.0177

Gnomad4 ASJ exome

AF:

0.0627

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0250

Gnomad4 FIN exome

AF:

0.00193

Gnomad4 NFE exome

AF:

0.0173

Gnomad4 OTH exome

AF:

0.0241

GnomAD4 genome

AF:

0.0169

AC:

2578

AN:

152348

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1215

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0126

Gnomad4 AMR

AF:

0.0195

Gnomad4 ASJ

AF:

0.0744

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.0271

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.0180

Gnomad4 OTH

AF:

0.0327

Alfa

AF:

0.0257

Hom.:

Bravo

AF:

0.0186

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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 specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

Cadd

Benign

4.4

Dann

Benign

0.46

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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