2-172474264-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000210.4(ITGA6):​c.985G>C​(p.Gly329Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

ITGA6
NM_000210.4 missense, splice_region

Scores

12
3
4
Splicing: ADA: 0.9882
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 10.0
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ITGA6NM_001394928.1 linkc.1102G>C p.Gly368Arg missense_variant, splice_region_variant Exon 7 of 26 ENST00000442250.6 NP_001381857.1
ITGA6NM_000210.4 linkc.985G>C p.Gly329Arg missense_variant, splice_region_variant Exon 6 of 26 ENST00000684293.1 NP_000201.2 P23229-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ITGA6ENST00000442250.6 linkc.1102G>C p.Gly368Arg missense_variant, splice_region_variant Exon 7 of 26 5 NM_001394928.1 ENSP00000406694.1 P23229-1
ITGA6ENST00000684293.1 linkc.985G>C p.Gly329Arg missense_variant, splice_region_variant Exon 6 of 26 NM_000210.4 ENSP00000508249.1 P23229-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460862
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726806
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.81
.;.;.;D;.;.
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D;D
MetaSVM
Pathogenic
0.85
D
MutationAssessor
Pathogenic
3.2
.;.;.;M;.;.
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-6.6
D;D;D;D;D;D
REVEL
Pathogenic
0.84
Sift
Benign
0.14
T;T;T;T;T;T
Sift4G
Benign
0.12
T;T;T;T;T;T
Polyphen
0.58
.;.;P;.;.;.
Vest4
0.88, 0.90, 0.93, 0.92, 0.92
MutPred
0.78
.;.;Gain of solvent accessibility (P = 0.0456);.;.;Gain of solvent accessibility (P = 0.0456);
MVP
0.90
MPC
1.2
ClinPred
0.99
D
GERP RS
5.4
Varity_R
0.64
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.86
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-173338992; API