rs3745925

chr19-501900-C-Achr19-501900-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_130760.3(MADCAM1):c.899C>A(p.Pro300His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,545,340 control chromosomes in the GnomAD database, including 35,668 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.21 (3561 hom., cov: 31)
  • Exomes 𝑓: 0.21 (32107 hom.)
• Consequence: MADCAM1 NM_130760.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0310

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029996634).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MADCAM1	NM_130760.3	c.899C>A	p.Pro300His	missense_variant	4/5	ENST00000215637.8
MADCAM1-AS1	XR_936221.4	n.515-276G>T		intron_variant, non_coding_transcript_variant
MADCAM1	NM_130762.3	c.668-2845C>A		intron_variant
MADCAM1-AS1	XR_007067073.1	n.515-276G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MADCAM1	ENST00000215637.8	c.899C>A	p.Pro300His	missense_variant	4/5	1	NM_130760.3	P2
MADCAM1-AS1	ENST00000592413.2	n.459-276G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32471 AN: 151774 Hom.: 3562 Cov.: 31

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.214 AC: 34007 AN: 158904 Hom.: 3814 AF XY: 0.209 AC XY: 17880 AN XY: 85562

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.197

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.336

Gnomad SAS exome AF: 0.138

Gnomad FIN exome AF: 0.264

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.212 AC: 295833 AN: 1393448 Hom.: 32107 Cov.: 47 AF XY: 0.210 AC XY: 144329 AN XY: 687900

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.196

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.341

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.256

Gnomad4 NFE exome AF: 0.211

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.214 AC: 32468 AN: 151892 Hom.: 3561 Cov.: 31 AF XY: 0.214 AC XY: 15895 AN XY: 74290

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.259

Gnomad4 EAS AF: 0.333

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.260

Gnomad4 NFE AF: 0.213

Gnomad4 OTH AF: 0.215

Alfa AF: 0.209 Hom.: 6127

Bravo AF: 0.213

TwinsUK AF: 0.198 AC: 733

ALSPAC AF: 0.210 AC: 809

ESP6500AA AF: 0.200 AC: 870

ESP6500EA AF: 0.201 AC: 1715

ExAC AF: 0.162 AC: 18891

Asia WGS AF: 0.204 AC: 711 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	17
Dann	Benign	0.18
DEOGEN2	Benign	0.025	T;.;T;T;T;T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.51	T;T;T;T;T;T;T
MetaRNN	Benign	0.0030	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.27	T
Sift4G	Uncertain	0.021	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;.
Vest4		0.26
MPC		0.81
ClinPred		0.015	T
GERP RS		-0.82
Varity_R		0.039
gMVP		0.26

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

Other links and lift over

dbSNP: rs3745925; hg19: chr19-501900; COSMIC: COSV53129903; COSMIC: COSV53129903;