19-501743-T-TCTCCCGACACCACCTCCCAGGAGCCTCCCGACACCACCTCCCAGGAGC

Position:

• chr19-501743-T-TCTCCCGACACCACCTCCCAGGAGCCTCCCGACACCACCTCCCAGGAGC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM4 BA1

The NM_130760.3(MADCAM1):​c.784_785insAGGAGCCTCCCGACACCACCTCCCAGGAGCCTCCCGACACCACCTCCC​(p.Ser261_Pro262insGlnGluProProAspThrThrSerGlnGluProProAspThrThrSer) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 77,340 control chromosomes in the GnomAD database, including 16,761 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.63 (16761 hom., cov: 36)
  • Exomes 𝑓: 0.46 (125193 hom.)
  • Failed GnomAD Quality Control
• Consequence: MADCAM1 NM_130760.3 inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.206

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_130760.3.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MADCAM1	NM_130760.3	c.784_785insAGGAGCCTCCCGACACCACCTCCCAGGAGCCTCCCGACACCACCTCCC	p.Ser261_Pro262insGlnGluProProAspThrThrSerGlnGluProProAspThrThrSer	inframe_insertion	4/5	ENST00000215637.8
MADCAM1-AS1	XR_936221.4	n.515-120_515-119insGCTCCTGGGAGGTGGTGTCGGGAGGCTCCTGGGAGGTGGTGTCGGGAG		intron_variant, non_coding_transcript_variant
MADCAM1	NM_130762.3	c.667+2960_668-2959insAGGAGCCTCCCGACACCACCTCCCAGGAGCCTCCCGACACCACCTCCC		intron_variant
MADCAM1-AS1	XR_007067073.1	n.515-120_515-119insGCTCCTGGGAGGTGGTGTCGGGAGGCTCCTGGGAGGTGGTGTCGGGAG		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MADCAM1	ENST00000215637.8	c.784_785insAGGAGCCTCCCGACACCACCTCCCAGGAGCCTCCCGACACCACCTCCC	p.Ser261_Pro262insGlnGluProProAspThrThrSerGlnGluProProAspThrThrSer	inframe_insertion	4/5	1	NM_130760.3	P2
MADCAM1-AS1	ENST00000592413.2	n.459-120_459-119insGCTCCTGGGAGGTGGTGTCGGGAGGCTCCTGGGAGGTGGTGTCGGGAG		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.629 AC: 48674 AN: 77340 Hom.: 16771 Cov.: 36

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.675

Gnomad AMR AF: 0.674

Gnomad ASJ AF: 0.697

Gnomad EAS AF: 0.710

Gnomad SAS AF: 0.717

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.553

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.607

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.460 AC: 339904 AN: 738958 Hom.: 125193 Cov.: 91 AF XY: 0.470 AC XY: 178631 AN XY: 379970

Gnomad4 AFR exome AF: 0.275

Gnomad4 AMR exome AF: 0.483

Gnomad4 ASJ exome AF: 0.559

Gnomad4 EAS exome AF: 0.703

Gnomad4 SAS exome AF: 0.547

Gnomad4 FIN exome AF: 0.730

Gnomad4 NFE exome AF: 0.410

Gnomad4 OTH exome AF: 0.526

GnomAD4 genome AF: 0.629 AC: 48656 AN: 77340 Hom.: 16761 Cov.: 36 AF XY: 0.625 AC XY: 22267 AN XY: 35620

Gnomad4 AFR AF: 0.371

Gnomad4 AMR AF: 0.674

Gnomad4 ASJ AF: 0.697

Gnomad4 EAS AF: 0.710

Gnomad4 SAS AF: 0.717

Gnomad4 FIN AF: 0.726

Gnomad4 NFE AF: 0.704

Gnomad4 OTH AF: 0.606

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hepatocellular carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Arun Kumar Laboratory, Indian Institute of Science

Jun 15, 2021

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555716199; hg19: chr19-501743;