Variant 19-498669-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_130760.3(MADCAM1):c.511G>A(p.Glu171Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,453,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

MADCAM1
NM_130760.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.157

Variant links:

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 links:

MADCAM1 (HGNC:):

MADCAM1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0757083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MADCAM1	NM_130760.3 linkuse as main transcript	c.511G>A	p.Glu171Lys	missense_variant	3/5	ENST00000215637.8	NP_570116.2	Q13477-1
MADCAM1	NM_130762.3 linkuse as main transcript	c.511G>A	p.Glu171Lys	missense_variant	3/4		NP_570118.1	Q13477-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MADCAM1	ENST00000215637.8 linkuse as main transcript	c.511G>A	p.Glu171Lys	missense_variant	3/5	1	NM_130760.3	ENSP00000215637.2		Q13477-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000568

AC:

AN:

88020

Hom.:

AF XY:

0.0000216

AC XY:

AN XY:

46400

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000138

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000903

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000968

AC:

126

AN:

1301280

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

633200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000161

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000161

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000114

Gnomad4 OTH exome

AF:

0.0000560

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.0000427

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2024

The c.511G>A (p.E171K) alteration is located in exon 3 (coding exon 3) of the MADCAM1 gene. This alteration results from a G to A substitution at nucleotide position 511, causing the glutamic acid (E) at amino acid position 171 to be replaced by a lysine (K). 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

Benign

0.22

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

.;T;T;T;.;T;.;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.83

T;T;T;T;T;T;T;T

M_CAP

Benign

0.0018

MetaRNN

Benign

0.076

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

.;.;.;.;L;L;.;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.3

.;.;.;.;N;N;N;.

REVEL

Benign

0.064

Sift

Benign

0.059

.;.;.;.;T;T;D;.

Sift4G

Benign

0.081

T;D;T;T;D;T;T;D

Polyphen

0.61

.;.;.;.;.;P;.;.

Vest4

0.28

MVP

0.20

MPC

0.25

ClinPred

0.092

GERP RS

-0.82

Varity_R

0.16

gMVP

0.35

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over