chr12-53192459-T-G

Variant names:

• chr12-53192459-T-G
• NM_000889.3:c.2026A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000889.3(ITGB7):​c.2026A>C​(p.Thr676Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGB7 NM_000889.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.168
• Publications: 0 publications found

Genes affected

ITGB7 (HGNC:6162): (integrin subunit beta 7) 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 dimers with an alpha4 chain or an alphaE chain and plays a role in leukocyte adhesion. Dimerization with alpha4 forms a homing receptor for migration of lymphocytes to the intestinal mucosa and Peyer's patches. Dimerization with alphaE permits binding to the ligand epithelial cadherin, a calcium-dependent adhesion molecule. Alternate splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Sep 2013]

ZNF740 (HGNC:27465): (zinc finger protein 740) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGB7	NM_000889.3	c.2026A>C	p.Thr676Pro	missense_variant	Exon 14 of 16	ENST00000267082.10	NP_000880.1
ZNF740	NM_001004304.4	c.*4869T>G		3_prime_UTR_variant	Exon 7 of 7	ENST00000416904.5	NP_001004304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB7	ENST00000267082.10	c.2026A>C	p.Thr676Pro	missense_variant	Exon 14 of 16	1	NM_000889.3	ENSP00000267082.4
ZNF740	ENST00000416904.5	c.*4869T>G		3_prime_UTR_variant	Exon 7 of 7	1	NM_001004304.4	ENSP00000409463.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2026A>C (p.T676P) alteration is located in exon 14 (coding exon 12) of the ITGB7 gene. This alteration results from a A to C substitution at nucleotide position 2026, causing the threonine (T) at amino acid position 676 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.61	.;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.8	L;L;.
PhyloP100		0.17
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N;N;.
REVEL	Uncertain	0.58
Sift	Benign	0.055	T;T;.
Sift4G	Benign	0.23	T;T;T
Polyphen		0.99	D;D;.
Vest4		0.46
MutPred		0.63		Gain of glycosylation at T673 (P = 0.0481);Gain of glycosylation at T673 (P = 0.0481);.;
MVP		0.89
MPC		1.1
ClinPred		0.71	D
GERP RS		3.1
PromoterAI		-0.018	Neutral
Varity_R		0.42
gMVP		0.85
Mutation Taster		=59/41	polymorphism

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

hg19: chr12-53586243;