Genetic Variant NM_015198.5:c.3703G>A (chr7-51025174-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_015198.5(COBL):c.3703G>A(p.Ala1235Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000081 in 1,382,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000087 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

COBL
NM_015198.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.03

Variant links:

Genes affected

COBL (HGNC:22199): (cordon-bleu WH2 repeat protein) This gene encodes a protein that contains WH2 domains (WASP, Wiskott-Aldrich syndrome protein, homology domain-2) that interact with actin. The encoded actin regulator protein is required for growth and assembly of brush border microvilli that play a role in maintaining intestinal homeostasis. A similar protein in mouse functions in midbrain neural tube closure. A pseudogene of this gene is located on chromosome X. [provided by RefSeq, Oct 2016]

COBL 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=0.041022837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COBL	NM_015198.5 link	c.3703G>A	p.Ala1235Thr	missense_variant	Exon 12 of 13	ENST00000265136.12	NP_056013.2	O75128-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COBL	ENST00000265136.12 link	c.3703G>A	p.Ala1235Thr	missense_variant	Exon 12 of 13	1	NM_015198.5	ENSP00000265136.7		O75128-1

Frequencies

GnomAD3 genomes

AF:

0.0000867

AC:

AN:

138330

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00658

Gnomad NFE

AF:

0.000140

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000104

AC:

AN:

249482

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

134906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000804

AC:

100

AN:

1244314

Hom.:

Cov.:

AF XY:

0.0000973

AC XY:

AN XY:

616728

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000550

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000356

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000771

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000867

AC:

AN:

138422

Hom.:

Cov.:

AF XY:

0.0000900

AC XY:

AN XY:

66698

show subpopulations

Gnomad4 AFR

AF:

0.0000262

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000140

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3703G>A (p.A1235T) alteration is located in exon 12 (coding exon 12) of the COBL gene. This alteration results from a G to A substitution at nucleotide position 3703, causing the alanine (A) at amino acid position 1235 to be replaced by a threonine (T). 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

0.071

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.75

CADD

Benign

5.4

DANN

Benign

0.95

DEOGEN2

Benign

0.021

T;T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.79

T;T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.041

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

.;.;N;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.72

N;N;N;.

REVEL

Benign

0.049

Sift

Benign

0.042

D;D;D;.

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.25, 0.21

.;.;B;B

Vest4

0.049, 0.093

MVP

0.17

MPC

0.076

ClinPred

0.020

GERP RS

1.8

Varity_R

0.028

gMVP

0.11

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