Variant 15-54013270-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001080534.3(UNC13C):c.367A>T(p.Ile123Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

UNC13C
NM_001080534.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21

Variant links:

Genes affected

UNC13C (HGNC:23149): (unc-13 homolog C) Predicted to enable calmodulin binding activity and syntaxin-1 binding activity. Predicted to be involved in several processes, including glutamatergic synaptic transmission; regulated exocytosis; and synaptic vesicle maturation. Predicted to be located in presynaptic active zone. Predicted to be active in several cellular components, including axon terminus; parallel fiber to Purkinje cell synapse; and presynaptic active zone cytoplasmic component. [provided by Alliance of Genome Resources, Apr 2022]

UNC13C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040586174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC13C	NM_001080534.3 linkuse as main transcript	c.367A>T	p.Ile123Phe	missense_variant	2/33	ENST00000260323.16	NP_001074003.1	Q8NB66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC13C	ENST00000260323.16 linkuse as main transcript	c.367A>T	p.Ile123Phe	missense_variant	2/33	5	NM_001080534.3	ENSP00000260323.11		Q8NB66
UNC13C	ENST00000647821.1 linkuse as main transcript	c.367A>T	p.Ile123Phe	missense_variant	2/32			ENSP00000497525.1		A0A3B3ISZ1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000282

AC:

AN:

248246

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134696

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461460

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

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:

0.0000342

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000828

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

Jan 19, 2022

The c.367A>T (p.I123F) alteration is located in exon 1 (coding exon 1) of the UNC13C gene. This alteration results from a A to T substitution at nucleotide position 367, causing the isoleucine (I) at amino acid position 123 to be replaced by a phenylalanine (F). 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

0.077

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.071

.;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.10

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.8

.;L

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.20

.;N

REVEL

Benign

0.17

Sift

Benign

0.039

.;D

Sift4G

Benign

0.20

.;T

Polyphen

0.0

.;B

Vest4

0.18

MutPred

0.086

Gain of phosphorylation at Y127 (P = 0.1209);Gain of phosphorylation at Y127 (P = 0.1209);

MVP

0.46

MPC

0.064

ClinPred

0.038

GERP RS

-0.47

Varity_R

0.080

gMVP

0.22

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