rs730882118

Variant names:

• chr2-160172665-A-T
• rs730882118
• NM_000888.5:c.825T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000888.5(ITGB6):​c.825T>A​(p.His275Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGB6 NM_000888.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.68
• Publications: 6 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 2-160172665-A-T is Pathogenic according to our data. Variant chr2-160172665-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 180684.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000888.5. 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
	ITGB6	NM_000888.5	MANE Select	c.825T>A	p.His275Gln	missense	Exon 6 of 15	NP_000879.2
	ITGB6	NM_001282353.2		c.825T>A	p.His275Gln	missense	Exon 7 of 16	NP_001269282.1
	ITGB6	NM_001282388.2		c.699T>A	p.His233Gln	missense	Exon 5 of 14	NP_001269317.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB6	ENST00000283249.7	TSL:1 MANE Select	c.825T>A	p.His275Gln	missense	Exon 6 of 15	ENSP00000283249.2
	ITGB6	ENST00000409872.1	TSL:1	c.825T>A	p.His275Gln	missense	Exon 7 of 16	ENSP00000386367.1
	ITGB6	ENST00000958494.1		c.825T>A	p.His275Gln	missense	Exon 6 of 16	ENSP00000628553.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Amelogenesis imperfecta type 1H (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		1.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.94		Loss of catalytic residue at D279 (P = 0.1351)
MVP		0.90
MPC		0.22
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.90
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs730882118; hg19: chr2-161029176;