chr19-501900-C-A

Variant names:

• chr19-501900-C-A
• rs3745925
• NM_130760.3:c.899C>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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: 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
• Publications: 24 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
MADCAM1	NM_130760.3	c.899C>A	p.Pro300His	missense_variant	Exon 4 of 5	ENST00000215637.8	NP_570116.2
MADCAM1	NM_130762.3	c.668-2845C>A		intron_variant	Intron 3 of 3		NP_570118.1
MADCAM1-AS1	XR_007067073.1	n.515-276G>T		intron_variant	Intron 1 of 1
MADCAM1-AS1	XR_936221.4	n.515-276G>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADCAM1	ENST00000215637.8	c.899C>A	p.Pro300His	missense_variant	Exon 4 of 5	1	NM_130760.3	ENSP00000215637.2

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

GnomAD2 exomes AF: 0.214 AC: 34007 AN: 158904 AF XY: 0.209

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 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

African (AFR) AF: 0.209 AC: 6542 AN: 31304

American (AMR) AF: 0.196 AC: 6789 AN: 34574

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 5702 AN: 23398

East Asian (EAS) AF: 0.341 AC: 12536 AN: 36742

South Asian (SAS) AF: 0.139 AC: 10774 AN: 77524

European-Finnish (FIN) AF: 0.256 AC: 12429 AN: 48510

Middle Eastern (MID) AF: 0.224 AC: 1219 AN: 5434

European-Non Finnish (NFE) AF: 0.211 AC: 227490 AN: 1078538

Other (OTH) AF: 0.215 AC: 12352 AN: 57424

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

African (AFR) AF: 0.204 AC: 8451 AN: 41418

American (AMR) AF: 0.188 AC: 2868 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 899 AN: 3470

East Asian (EAS) AF: 0.333 AC: 1718 AN: 5158

South Asian (SAS) AF: 0.125 AC: 604 AN: 4820

European-Finnish (FIN) AF: 0.260 AC: 2743 AN: 10536

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14489 AN: 67898

Other (OTH) AF: 0.215 AC: 455 AN: 2112

Alfa AF: 0.210 Hom.: 9153

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
MutationAssessor	Benign	0.81	.;.;.;.;.;L;.
PhyloP100		-0.031
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	.;.;.;.;.;N;.
REVEL	Benign	0.15
Sift	Benign	0.58	.;.;.;.;.;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
Mutation Taster		=97/3	polymorphism (auto)

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