Variant chr19-17606104-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_001080421.3(UNC13A):c.5062A>G(p.Lys1688Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

UNC13A
NM_001080421.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.95

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC13A	NM_001080421.3 linkuse as main transcript	c.5062A>G	p.Lys1688Glu	missense_variant	44/44	ENST00000519716.7	NP_001073890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
UNC13A	ENST00000519716.7 linkuse as main transcript	c.5062A>G	p.Lys1688Glu	missense_variant	44/44	5	NM_001080421.3	ENSP00000429562	A2
UNC13A	ENST00000551649.5 linkuse as main transcript	c.5119A>G	p.Lys1707Glu	missense_variant	45/45	5		ENSP00000447236	P3
UNC13A	ENST00000552293.5 linkuse as main transcript	c.5044A>G	p.Lys1682Glu	missense_variant	42/42	5		ENSP00000447572	A2
UNC13A	ENST00000550896.1 linkuse as main transcript	c.4981A>G	p.Lys1661Glu	missense_variant	40/40	5		ENSP00000446831	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1443890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717772

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

UNC13A-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 27, 2023

The UNC13A c.5062A>G variant is predicted to result in the amino acid substitution p.Lys1688Glu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. 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

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.;T;.

Eigen

Uncertain

0.37

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.81

D;D;D;D

MetaSVM

Uncertain

0.42

MutationAssessor

Pathogenic

3.3

M;.;.;.

MutationTaster

Benign

0.98

D;D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.4

D;D;D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.81

MutPred

0.34

Loss of ubiquitination at K1688 (P = 0.0023);.;.;.;

MVP

0.82

MPC

2.3

ClinPred

0.99

GERP RS

1.9

Varity_R

0.59

gMVP

0.85

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over