19-498717-G-C

Variant names:

• chr19-498717-G-C
• rs762488496
• NM_130760.3:c.559G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_130760.3(MADCAM1):​c.559G>C​(p.Glu187Gln) 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 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MADCAM1 NM_130760.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.41

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030760556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MADCAM1	NM_130760.3	c.559G>C	p.Glu187Gln	missense_variant	Exon 3 of 5	ENST00000215637.8	NP_570116.2
MADCAM1	NM_130762.3	c.559G>C	p.Glu187Gln	missense_variant	Exon 3 of 4		NP_570118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADCAM1	ENST00000215637.8	c.559G>C	p.Glu187Gln	missense_variant	Exon 3 of 5	1	NM_130760.3	ENSP00000215637.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000129 AC: 1 AN: 77220 Hom.: 0 AF XY: 0.0000244 AC XY: 1 AN XY: 40956

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000134

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1305254 Hom.: 0 Cov.: 58 AF XY: 0.00 AC XY: 0 AN XY: 636340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000930 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.12
DANN	Benign	0.63
DEOGEN2	Benign	0.0091	.;T;T;T;.;T;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.65	T;T;T;T;T;T;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.031	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.20	.;.;.;.;N;N;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.12	.;.;.;.;N;N;N;.
REVEL	Benign	0.013
Sift	Benign	0.62	.;.;.;.;T;T;T;.
Sift4G	Benign	0.49	T;T;T;T;T;T;T;T
Polyphen		0.046	.;.;.;.;.;B;.;.
Vest4		0.043
MutPred		0.36		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;Gain of sheet (P = 0.039);
MVP		0.067
MPC		0.27
ClinPred		0.029	T
GERP RS		-8.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.13
gMVP		0.36

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: rs762488496; hg19: chr19-498717;