Variant 19-17606074-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_001080421.3(UNC13A):c.5092G>A(p.Gly1698Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000228 in 1,580,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

UNC13A
NM_001080421.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.57

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 Benign. Variant got -7 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=0.03046143).

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC13A	NM_001080421.3 linkuse as main transcript	c.5092G>A	p.Gly1698Ser	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.5092G>A	p.Gly1698Ser	missense_variant	44/44	5	NM_001080421.3	ENSP00000429562	A2
UNC13A	ENST00000551649.5 linkuse as main transcript	c.5149G>A	p.Gly1717Ser	missense_variant	45/45	5		ENSP00000447236	P3
UNC13A	ENST00000552293.5 linkuse as main transcript	c.5074G>A	p.Gly1692Ser	missense_variant	42/42	5		ENSP00000447572	A2
UNC13A	ENST00000550896.1 linkuse as main transcript	c.5011G>A	p.Gly1671Ser	missense_variant	40/40	5		ENSP00000446831	A2

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000105

AC:

AN:

1428034

Hom.:

Cov.:

AF XY:

0.0000127

AC XY:

AN XY:

709318

show subpopulations

Gnomad4 AFR exome

AF:

0.000440

Gnomad4 AMR exome

AF:

0.0000242

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000197

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000138

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.000274

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000169

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.5092G>A (p.G1698S) alteration is located in exon 44 (coding exon 44) of the UNC13A gene. This alteration results from a G to A substitution at nucleotide position 5092, causing the glycine (G) at amino acid position 1698 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.;T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.80

T;T;T;T

M_CAP

Benign

0.072

MetaRNN

Benign

0.030

T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-1.1

N;.;.;.

MutationTaster

Benign

0.97

N;N;N;N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.47

T;T;T;T

Sift4G

Benign

0.73

T;T;T;T

Polyphen

0.38

B;.;.;.

Vest4

0.037

MVP

0.082

MPC

0.84

ClinPred

0.11

GERP RS

2.1

Varity_R

0.094

gMVP

0.27

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