dbSNP rs730880298: ITGB6:p.Pro196Ser (chr2-160195376-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM5PP3_Strong

The NM_000888.5(ITGB6):c.586C>T(p.Pro196Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P196T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ITGB6
NM_000888.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 10.0

Publications

6 publications found

Variant links:

Genes affected

ITGB6 (HGNC:6161): (integrin subunit beta 6) This gene encodes a protein that is a member of the integrin superfamily. Members of this family are adhesion receptors that function in signaling from the extracellular matrix to the cell. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. The encoded protein forms a dimer with an alpha v chain and this heterodimer can bind to ligands like fibronectin and transforming growth factor beta 1. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ITGB6 Gene-Disease associations (from GenCC):

amelogenesis imperfecta type 1H
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
amelogenesis imperfecta type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
amelogenesis imperfecta, type 3A
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ITGB6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a domain VWFA (size 240) in uniprot entity ITB6_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000888.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-160195376-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180686.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGB6	NM_000888.5 link	c.586C>T	p.Pro196Ser	missense_variant	Exon 4 of 15	ENST00000283249.7	NP_000879.2	P18564-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB6	ENST00000283249.7 link	c.586C>T	p.Pro196Ser	missense_variant	Exon 4 of 15	1	NM_000888.5	ENSP00000283249.2		P18564-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.000151

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111954

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;.;.;.;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D;D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.9

H;.;.;H;H

PhyloP100

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.7

D;.;D;D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;.;D;D;D

Sift4G

Uncertain

0.018

D;D;D;D;D

Polyphen

0.82

P;.;P;.;P

Vest4

0.87

MutPred

0.87

Loss of catalytic residue at P196 (P = 0.0099);.;.;Loss of catalytic residue at P196 (P = 0.0099);Loss of catalytic residue at P196 (P = 0.0099);

MVP

0.86

MPC

0.15

ClinPred

1.0

GERP RS

6.0

Varity_R

0.93

gMVP

0.82

Mutation Taster

=14/86

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over