19-498781-T-G

Position:

• chr19-498781-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_130760.3(MADCAM1):​c.623T>G​(p.Met208Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MADCAM1 NM_130760.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98

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-AS1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MADCAM1	NM_130760.3	c.623T>G	p.Met208Arg	missense_variant	3/5	ENST00000215637.8	NP_570116.2
MADCAM1	NM_130762.3	c.623T>G	p.Met208Arg	missense_variant	3/4		NP_570118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MADCAM1	ENST00000215637.8	c.623T>G	p.Met208Arg	missense_variant	3/5	1	NM_130760.3	ENSP00000215637.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

The c.623T>G (p.M208R) alteration is located in exon 3 (coding exon 3) of the MADCAM1 gene. This alteration results from a T to G substitution at nucleotide position 623, causing the methionine (M) at amino acid position 208 to be replaced by an arginine (R). 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	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;T;T;T;.;T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	.;.;.;.;L;L;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.2	.;.;.;.;D;D;D;.
REVEL	Benign	0.23
Sift	Uncertain	0.0010	.;.;.;.;D;D;D;.
Sift4G	Uncertain	0.011	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;.;.
Vest4		0.76
MutPred		0.82		Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);.;Loss of sheet (P = 0.0104);
MVP		0.20
MPC		1.0
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.96
gMVP		0.74

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.

Other links and lift over

hg19: chr19-498781;