chr19-504813-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_130760.3(MADCAM1):c.997C>T(p.Leu333Phe) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Consequence
MADCAM1
NM_130760.3 missense
NM_130760.3 missense
Scores
2
13
Clinical Significance
Conservation
PhyloP100: 0.105
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]
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ACMG classification
Classification made for transcript
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=0.05377984).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MADCAM1 | NM_130760.3 | c.997C>T | p.Leu333Phe | missense_variant | 5/5 | ENST00000215637.8 | |
MADCAM1-AS1 | XR_936221.4 | n.514+2563G>A | intron_variant, non_coding_transcript_variant | ||||
MADCAM1 | NM_130762.3 | c.736C>T | p.Leu246Phe | missense_variant | 4/4 | ||
MADCAM1-AS1 | XR_007067073.1 | n.514+2563G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MADCAM1 | ENST00000215637.8 | c.997C>T | p.Leu333Phe | missense_variant | 5/5 | 1 | NM_130760.3 | P2 | |
MADCAM1-AS1 | ENST00000592413.2 | n.458+2563G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250272Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135686
GnomAD3 exomes
AF:
AC:
1
AN:
250272
Hom.:
AF XY:
AC XY:
1
AN XY:
135686
Gnomad AFR exome
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GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ExAC
?
AF:
AC:
1
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 | Oct 26, 2022 | The c.997C>T (p.L333F) alteration is located in exon 5 (coding exon 5) of the MADCAM1 gene. This alteration results from a C to T substitution at nucleotide position 997, causing the leucine (L) at amino acid position 333 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.;T;T;T;.;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T;T;T;T;T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N
PrimateAI
Benign
T
Sift4G
Uncertain
D;T;T;T;T;T;T;D;T
Polyphen
0.21
.;.;.;.;.;.;B;.;.
Vest4
MutPred
0.29
.;.;.;.;.;.;Gain of catalytic residue at L333 (P = 0.1118);.;.;
MVP
MPC
0.55
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at