19-501701-G-GACACCACCTCCCCGGAGCCTCCCA

Variant summary

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

The NM_130760.3(MADCAM1):c.717_718insCCTCCCAACACCACCTCCCCGGAG(p.Glu239_Ser240insProProAsnThrThrSerProGlu) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 133,540 control chromosomes in the GnomAD database, including 5,441 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.28 (5441 hom., cov: 33)
  • Exomes 𝑓: 0.22 (51538 hom.)
  • Failed GnomAD Quality Control
• Consequence: MADCAM1 NM_130760.3 inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -5.20

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 (AMR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MADCAM1	NM_130760.3	c.717_718insCCTCCCAACACCACCTCCCCGGAG	p.Glu239_Ser240insProProAsnThrThrSerProGlu	inframe_insertion	4/5	ENST00000215637.8
MADCAM1-AS1	XR_936221.4	n.515-78_515-77insTGGGAGGCTCCGGGGAGGTGGTGT		intron_variant, non_coding_transcript_variant
MADCAM1	NM_130762.3	c.667+2893_667+2894insCCTCCCAACACCACCTCCCCGGAG		intron_variant
MADCAM1-AS1	XR_007067073.1	n.515-78_515-77insTGGGAGGCTCCGGGGAGGTGGTGT		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MADCAM1	ENST00000215637.8	c.717_718insCCTCCCAACACCACCTCCCCGGAG	p.Glu239_Ser240insProProAsnThrThrSerProGlu	inframe_insertion	4/5	1	NM_130760.3	P2
MADCAM1-AS1	ENST00000592413.2	n.459-78_459-77insTGGGAGGCTCCGGGGAGGTGGTGT		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.275 AC: 36755 AN: 133476 Hom.: 5444 Cov.: 33

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.273

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.224 AC: 255180 AN: 1139466 Hom.: 51538 Cov.: 58 AF XY: 0.230 AC XY: 131436 AN XY: 570350

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.308

Gnomad4 ASJ exome AF: 0.248

Gnomad4 EAS exome AF: 0.303

Gnomad4 SAS exome AF: 0.273

Gnomad4 FIN exome AF: 0.402

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.275 AC: 36755 AN: 133540 Hom.: 5441 Cov.: 33 AF XY: 0.276 AC XY: 17572 AN XY: 63776

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.338

Gnomad4 ASJ AF: 0.300

Gnomad4 EAS AF: 0.313

Gnomad4 SAS AF: 0.313

Gnomad4 FIN AF: 0.350

Gnomad4 NFE AF: 0.330

Gnomad4 OTH AF: 0.273

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: rs1555716175; hg19: chr19-501701;