19-497985-G-A

Variant names:

• chr19-497985-G-A
• rs920314016
• NM_130760.3:c.205G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_130760.3(MADCAM1):​c.205G>A​(p.Ala69Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000223 in 1,346,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A69S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: MADCAM1 NM_130760.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.99
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.064605564).

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.205G>A	p.Ala69Thr	missense	Exon 2 of 5	NP_570116.2	Q13477-1
	MADCAM1	NM_130762.3		c.205G>A	p.Ala69Thr	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.205G>A	p.Ala69Thr	missense	Exon 2 of 5	ENSP00000215637.2	Q13477-1
	MADCAM1	ENST00000346144.8	TSL:1	c.205G>A	p.Ala69Thr	missense	Exon 2 of 4	ENSP00000304247.2	Q13477-3
	MADCAM1	ENST00000382683.8	TSL:1	c.53-511G>A		intron	N/A	ENSP00000372130.4	Q13477-4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000223 AC: 3 AN: 1346366 Hom.: 0 Cov.: 32 AF XY: 0.00000301 AC XY: 2 AN XY: 663908

African (AFR) AF: 0.00 AC: 0 AN: 28178

American (AMR) AF: 0.00 AC: 0 AN: 31942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23696

East Asian (EAS) AF: 0.00 AC: 0 AN: 32116

South Asian (SAS) AF: 0.00 AC: 0 AN: 74764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4406

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1062054

Other (OTH) AF: 0.0000178 AC: 1 AN: 56136

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-2.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.15
Sift	Benign	0.28	T
Sift4G	Benign	0.13	T
Polyphen		0.37	B
Vest4		0.063
MutPred		0.13		Loss of sheet (P = 0.0457)
MVP		0.14
MPC		0.22
ClinPred		0.11	T
GERP RS		-3.4
Varity_R		0.26
gMVP		0.11
Mutation Taster		=85/15	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: rs920314016; hg19: chr19-497985;