rs201055917

Variant names:

• chr2-172504202-GA-G
• rs201055917
• NM_001394928.1:c.3351delA

Your query was ambiguous. Multiple possible variants found:

• chr2-172504202-GA-G
• chr2-172504202-GA-GAA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001394928.1(ITGA6):​c.3351delA​(p.Lys1117AsnfsTer48) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000316 in 1,580,262 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ITGA6 NM_001394928.1 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.72
• Publications: 6 publications found

Genes affected

ITGA6 (HGNC:6142): (integrin subunit alpha 6) The gene encodes a member of the integrin alpha chain family of proteins. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain that function in cell surface adhesion and signaling. The encoded preproprotein is proteolytically processed to generate light and heavy chains that comprise the alpha 6 subunit. This subunit may associate with a beta 1 or beta 4 subunit to form an integrin that interacts with extracellular matrix proteins including members of the laminin family. The alpha 6 beta 4 integrin may promote tumorigenesis, while the alpha 6 beta 1 integrin may negatively regulate erbB2/HER2 signaling. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

ITGA6-AS1 (HGNC:40308): (ITGA6 antisense RNA 1)

PDK1-AS1 (HGNC:40441): (PDK1 and ITGA6 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0124 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394928.1. 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
	ITGA6	NM_001394928.1	MANE Plus Clinical	c.3351delA	p.Lys1117AsnfsTer48	frameshift	Exon 26 of 26	NP_001381857.1	P23229-1
	ITGA6	NM_000210.4	MANE Select	c.*142delA		3_prime_UTR	Exon 26 of 26	NP_000201.2	P23229-2
	ITGA6	NM_001079818.3		c.3234delA	p.Lys1078AsnfsTer48	frameshift	Exon 25 of 25	NP_001073286.1	P23229-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA6	ENST00000442250.6	TSL:5 MANE Plus Clinical	c.3351delA	p.Lys1117AsnfsTer48	frameshift	Exon 26 of 26	ENSP00000406694.1	P23229-1
	ITGA6	ENST00000684293.1	MANE Select	c.*142delA		3_prime_UTR	Exon 26 of 26	ENSP00000508249.1	P23229-2
	ITGA6	ENST00000264107.12	TSL:1	c.*142delA		3_prime_UTR	Exon 26 of 26	ENSP00000264107.8	A0A8C8KBL6

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150374 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.00000998 AC: 2 AN: 200476 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000351

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1429888 Hom.: 0 Cov.: 31 AF XY: 0.00000423 AC XY: 3 AN XY: 708650

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32612

American (AMR) AF: 0.00 AC: 0 AN: 40148

Ashkenazi Jewish (ASJ) AF: 0.0000392 AC: 1 AN: 25488

East Asian (EAS) AF: 0.00 AC: 0 AN: 38520

South Asian (SAS) AF: 0.00 AC: 0 AN: 81648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1094920

Other (OTH) AF: 0.00 AC: 0 AN: 59246

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0104607), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150374 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73340

African (AFR) AF: 0.00 AC: 0 AN: 40904

American (AMR) AF: 0.00 AC: 0 AN: 15102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10194

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67568

Other (OTH) AF: 0.000482 AC: 1 AN: 2076

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=7/193	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs201055917; hg19: chr2-173368930; COSMIC: COSV51221902; COSMIC: COSV51221902;