Genetic Variant MADCAM1:p.Pro300Arg (chr19-501900-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_130760.3(MADCAM1):c.899C>G(p.Pro300Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

MADCAM1
NM_130760.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0310

Publications

24 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.088134974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MADCAM1	NM_130760.3 link	c.899C>G	p.Pro300Arg	missense_variant	Exon 4 of 5	ENST00000215637.8	NP_570116.2	Q13477-1
MADCAM1	NM_130762.3 link	c.668-2845C>G		intron_variant	Intron 3 of 3		NP_570118.1	Q13477-3
MADCAM1-AS1	XR_007067073.1 link	n.515-276G>C		intron_variant	Intron 1 of 1
MADCAM1-AS1	XR_936221.4 link	n.515-276G>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADCAM1	ENST00000215637.8 link	c.899C>G	p.Pro300Arg	missense_variant	Exon 4 of 5	1	NM_130760.3	ENSP00000215637.2		Q13477-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

158904

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1394120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688256

show subpopulations

African (AFR)

AF:

0.0000319

AC:

AN:

31318

American (AMR)

AF:

0.00

AC:

AN:

34644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23422

East Asian (EAS)

AF:

0.00

AC:

AN:

36762

South Asian (SAS)

AF:

0.00

AC:

AN:

77564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5440

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078956

Other (OTH)

AF:

0.00

AC:

AN:

57454

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

9153

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.026

T;.;T;T;T;T;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0061

LIST_S2

Benign

0.70

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

M_CAP

Benign

0.0050

MetaRNN

Benign

0.088

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

.;.;.;.;.;L;.

PhyloP100

-0.031

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.2

.;.;.;.;.;N;.

REVEL

Benign

0.11

Sift

Benign

0.53

.;.;.;.;.;T;.

Sift4G

Uncertain

0.058

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

Polyphen

0.96

.;.;.;.;.;P;.

Vest4

0.22

MutPred

0.29

.;.;.;.;.;Gain of MoRF binding (P = 0.0014);.;

MVP

0.21

MPC

0.70

ClinPred

0.19

GERP RS

-0.82

Varity_R

0.020

gMVP

0.30

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over