Variant chr19-17606263-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001080421.3(UNC13A):c.4903C>G(p.Leu1635Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,395,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

UNC13A
NM_001080421.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.54

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13107586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC13A	NM_001080421.3 link	c.4903C>G	p.Leu1635Val	missense_variant	44/44	ENST00000519716.7	NP_001073890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
UNC13A	ENST00000519716.7 link	c.4903C>G	p.Leu1635Val	missense_variant	44/44	5	NM_001080421.3	ENSP00000429562.2	Q9UPW8
UNC13A	ENST00000551649.5 link	c.4960C>G	p.Leu1654Val	missense_variant	45/45	5		ENSP00000447236.1	F8W059
UNC13A	ENST00000552293.5 link	c.4885C>G	p.Leu1629Val	missense_variant	42/42	5		ENSP00000447572.1	F8W0P6
UNC13A	ENST00000550896.1 link	c.4822C>G	p.Leu1608Val	missense_variant	40/40	5		ENSP00000446831.1	F8VZH8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1395046

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688272

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

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:

9.27e-7

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

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2024

The c.4903C>G (p.L1635V) alteration is located in exon 44 (coding exon 44) of the UNC13A gene. This alteration results from a C to G substitution at nucleotide position 4903, causing the leucine (L) at amino acid position 1635 to be replaced by a valine (V). 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

0.10

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.076

T;.;T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.64

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Benign

0.0080

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.28

N;.;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.010

N;N;N;N

REVEL

Benign

0.089

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0010

B;.;.;.

Vest4

0.17

MutPred

0.50

Loss of sheet (P = 0.0817);.;.;.;

MVP

0.068

MPC

0.86

ClinPred

0.32

GERP RS

1.9

Varity_R

0.072

gMVP

0.35

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