chr19-497985-G-T

Variant names:

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

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>T​(p.Ala69Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000133 in 1,498,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: MADCAM1 NM_130760.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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=0.029642045).

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>T	p.Ala69Ser	missense	Exon 2 of 5	NP_570116.2	Q13477-1
	MADCAM1	NM_130762.3		c.205G>T	p.Ala69Ser	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>T	p.Ala69Ser	missense	Exon 2 of 5	ENSP00000215637.2	Q13477-1
	MADCAM1	ENST00000346144.8	TSL:1	c.205G>T	p.Ala69Ser	missense	Exon 2 of 4	ENSP00000304247.2	Q13477-3
	MADCAM1	ENST00000382683.8	TSL:1	c.53-511G>T		intron	N/A	ENSP00000372130.4	Q13477-4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1346368 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 663910

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

American (AMR) AF: 0.0000313 AC: 1 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: 0.00 AC: 0 AN: 1062056

Other (OTH) AF: 0.00 AC: 0 AN: 56136

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74270

African (AFR) AF: 0.00 AC: 0 AN: 41402

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.1
DANN	Benign	0.92
DEOGEN2	Benign	0.0057	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-2.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.083
Sift	Benign	0.90	T
Sift4G	Benign	0.48	T
Polyphen		0.029	B
Vest4		0.062
MutPred		0.11		Gain of disorder (P = 0.0437)
MVP		0.076
MPC		0.21
ClinPred		0.051	T
GERP RS		-3.4
Varity_R		0.27
gMVP		0.12
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;