rs960767931

Variant names:

• chr19-497929-C-T
• rs960767931
• NM_130760.3:c.149C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_130760.3(MADCAM1):​c.149C>T​(p.Ala50Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000706 in 1,417,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: MADCAM1 NM_130760.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.932
• Publications: 0 publications found

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:55315): (MADCAM1 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09994528).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130760.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADCAM1	NM_130760.3	MANE Select	c.149C>T	p.Ala50Val	missense	Exon 2 of 5	NP_570116.2	Q13477-1
	MADCAM1	NM_130762.3		c.149C>T	p.Ala50Val	missense	Exon 2 of 4	NP_570118.1	Q13477-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADCAM1	ENST00000215637.8	TSL:1 MANE Select	c.149C>T	p.Ala50Val	missense	Exon 2 of 5	ENSP00000215637.2	Q13477-1
	MADCAM1	ENST00000346144.8	TSL:1	c.149C>T	p.Ala50Val	missense	Exon 2 of 4	ENSP00000304247.2	Q13477-3
	MADCAM1	ENST00000382683.8	TSL:1	c.53-567C>T		intron	N/A	ENSP00000372130.4	Q13477-4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152030 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 46892 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: 7.91e-7 AC: 1 AN: 1264932 Hom.: 0 Cov.: 32 AF XY: 0.00000161 AC XY: 1 AN XY: 621972

African (AFR) AF: 0.00 AC: 0 AN: 24990

American (AMR) AF: 0.00 AC: 0 AN: 17106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19894

East Asian (EAS) AF: 0.00 AC: 0 AN: 28144

South Asian (SAS) AF: 0.00 AC: 0 AN: 63180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3696

European-Non Finnish (NFE) AF: 9.76e-7 AC: 1 AN: 1024376

Other (OTH) AF: 0.00 AC: 0 AN: 52148

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74370

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000217 AC: 9 AN: 41532

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67940

Other (OTH) AF: 0.00 AC: 0 AN: 2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.93
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.032
Sift	Benign	0.17	T
Sift4G	Benign	0.11	T
Polyphen		0.16	B
Vest4		0.051
MutPred		0.18		Gain of sheet (P = 0.0827)
MVP		0.030
MPC		0.28
ClinPred		0.054	T
GERP RS		1.8
Varity_R		0.050
gMVP		0.18
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs960767931; hg19: chr19-497929;