19-497884-T-C

Position:

• chr19-497884-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_130760.3(MADCAM1):​c.104T>C​(p.Val35Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,201,374 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: MADCAM1 NM_130760.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.328

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MADCAM1	NM_130760.3	c.104T>C	p.Val35Ala	missense_variant	2/5	ENST00000215637.8	NP_570116.2
MADCAM1	NM_130762.3	c.104T>C	p.Val35Ala	missense_variant	2/4		NP_570118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MADCAM1	ENST00000215637.8	c.104T>C	p.Val35Ala	missense_variant	2/5	1	NM_130760.3	ENSP00000215637.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000166 AC: 2 AN: 1201374 Hom.: 0 Cov.: 32 AF XY: 0.00000171 AC XY: 1 AN XY: 585186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000951

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: 0.0000204

GnomAD4 genome Cov.: 34

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

Nov 09, 2024

The c.104T>C (p.V35A) alteration is located in exon 2 (coding exon 2) of the MADCAM1 gene. This alteration results from a T to C substitution at nucleotide position 104, causing the valine (V) at amino acid position 35 to be replaced by an alanine (A). 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.050	.;T;T;T;.;T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.033
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.69	T;T;T;T;T;T;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.9	.;.;.;.;L;L;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.4	.;.;.;.;N;N;.
REVEL	Benign	0.16
Sift	Benign	0.061	.;.;.;.;T;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;.
Vest4		0.41
MutPred		0.44		Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);
MVP		0.61
MPC		0.26
ClinPred		0.58	D
GERP RS		3.0
Varity_R		0.36
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1978293027; hg19: chr19-497884;