Variant 19-496528-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_130760.3(MADCAM1):c.29C>T(p.Ala10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,302,154 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000097 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000092 ( 1 hom. )

Consequence

MADCAM1
NM_130760.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.953

Variant links:

Genes affected

MADCAM1 (HGNC:6765): (mucosal vascular addressin cell adhesion molecule 1) The protein encoded by this gene is an endothelial cell adhesion molecule that interacts preferentially with the leukocyte beta7 integrin LPAM-1 (alpha4beta7), L-selectin, and VLA-4 (alpha4beta1) on myeloid cells to direct leukocytes into mucosal and inflamed tissues. It is a member of the immunoglobulin family and is similar to ICAM1 and VCAM1. At least seven alternatively spliced transcripts encoding different protein isoforms have been found for this gene, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jul 2008]

MADCAM1 links:

MADCAM1-AS1 (HGNC:55315): (MADCAM1 antisense RNA 1)

MADCAM1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MADCAM1	NM_130760.3 linkuse as main transcript	c.29C>T	p.Ala10Val	missense_variant	1/5	ENST00000215637.8
MADCAM1	NM_130762.3 linkuse as main transcript	c.29C>T	p.Ala10Val	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MADCAM1	ENST00000215637.8 linkuse as main transcript	c.29C>T	p.Ala10Val	missense_variant	1/5	1	NM_130760.3	P2	Q13477-1
MADCAM1-AS1	ENST00000592413.2 linkuse as main transcript	n.542+5013G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000970

AC:

AN:

144402

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000156

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000698

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00102

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00102

GnomAD3 exomes

AF:

0.000150

AC:

AN:

113000

Hom.:

AF XY:

0.0000981

AC XY:

AN XY:

61192

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000103

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00196

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000543

GnomAD4 exome

AF:

0.0000924

AC:

107

AN:

1157752

Hom.:

Cov.:

AF XY:

0.0000703

AC XY:

AN XY:

554432

show subpopulations

Gnomad4 AFR exome

AF:

0.0000803

Gnomad4 AMR exome

AF:

0.0000581

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000790

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000315

Gnomad4 OTH exome

AF:

0.00167

GnomAD4 genome

AF:

0.0000970

AC:

AN:

144402

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

69944

show subpopulations

Gnomad4 AFR

AF:

0.000156

Gnomad4 AMR

AF:

0.0000698

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00102

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00102

Alfa

AF:

0.000272

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000169

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3478

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

Jun 30, 2023

The c.29C>T (p.A10V) alteration is located in exon 1 (coding exon 1) of the MADCAM1 gene. This alteration results from a C to T substitution at nucleotide position 29, causing the alanine (A) at amino acid position 10 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

0.23

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

Cadd

Benign

9.5

Dann

Benign

0.73

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0050

LIST_S2

Benign

0.56

T;T;T;T;T;T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.0089

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.54

Sift4G

Benign

0.14

T;D;T;T;T;D;T;T

Polyphen

0.20

.;.;.;.;.;B;.;.

Vest4

0.20

MVP

0.20

MPC

0.22

ClinPred

0.016

GERP RS

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.027

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.29

Position offset: -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