Variant 19-17606311-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001080421.3(UNC13A):c.4855G>A(p.Val1619Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000634 in 1,549,630 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00065 ( 1 hom. )

Consequence

UNC13A
NM_001080421.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.47

Variant links:

Genes affected

UNC13A (HGNC:23150): (unc-13 homolog A) This gene encodes a member of the UNC13 family. UNC13 proteins bind to phorbol esters and diacylglycerol and play important roles in neurotransmitter release at synapses. Single nucleotide polymorphisms in this gene may be associated with sporadic amyotrophic lateral sclerosis. [provided by RefSeq, Feb 2012]

UNC13A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), UNC13A. . Gene score misZ 5.6267 (greater than the threshold 3.09). Trascript score misZ 5.1925 (greater than threshold 3.09). GenCC has associacion of gene with congenital nervous system disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.07250783).

BS2

High AC in GnomAd4 at 73 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC13A	NM_001080421.3 linkuse as main transcript	c.4855G>A	p.Val1619Met	missense_variant	44/44	ENST00000519716.7	NP_001073890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC13A	ENST00000519716.7 linkuse as main transcript	c.4855G>A	p.Val1619Met	missense_variant	44/44	5	NM_001080421.3	ENSP00000429562	A2

Frequencies

GnomAD3 genomes

AF:

0.000479

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000436

AC:

AN:

144656

Hom.:

AF XY:

0.000447

AC XY:

AN XY:

78294

show subpopulations

Gnomad AFR exome

AF:

0.000282

Gnomad AMR exome

AF:

0.0000403

Gnomad ASJ exome

AF:

0.000241

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000803

Gnomad NFE exome

AF:

0.000832

Gnomad OTH exome

AF:

0.000712

GnomAD4 exome

AF:

0.000651

AC:

909

AN:

1397266

Hom.:

Cov.:

AF XY:

0.000647

AC XY:

446

AN XY:

689578

show subpopulations

Gnomad4 AFR exome

AF:

0.000222

Gnomad4 AMR exome

AF:

0.0000834

Gnomad4 ASJ exome

AF:

0.000159

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00128

Gnomad4 NFE exome

AF:

0.000741

Gnomad4 OTH exome

AF:

0.000620

GnomAD4 genome

AF:

0.000479

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00169

Gnomad4 NFE

AF:

0.000676

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000630

Hom.:

Bravo

AF:

0.000393

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000342

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

UNC13A-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 15, 2023

The UNC13A c.4855G>A variant is predicted to result in the amino acid substitution p.Val1619Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.099% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-17717120-C-T). A different variant affecting the same amino acid (p.Val1619Gly) was reported in the homozygous state in an individual with epileptic encephalopathy with intractable seizures and global developmental delay, however, no additional information was provided (Table S1 and S3, Al-Dewik et al. 2019. PubMed ID: 30919572). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.44

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.;T;.

Eigen

Benign

-0.057

Eigen_PC

Benign

-0.020

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.073

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.;.;.

MutationTaster

Benign

0.96

D;D;D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.5

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.091

T;T;T;T

Sift4G

Uncertain

0.056

T;T;T;T

Polyphen

0.45

B;.;.;.

Vest4

0.32

MVP

0.16

MPC

1.6

ClinPred

0.085

GERP RS

3.0

Varity_R

0.21

gMVP

0.54

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