10-32912060-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_002211.4(ITGB1):c.1534A>C(p.Met512Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ITGB1 NM_002211.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

Genes affected

ITGB1 (HGNC:6153): (integrin subunit beta 1) Integrins are heterodimeric proteins made up of alpha and beta subunits. At least 18 alpha and 8 beta subunits have been described in mammals. Integrin family members are membrane receptors involved in cell adhesion and recognition in a variety of processes including embryogenesis, hemostasis, tissue repair, immune response and metastatic diffusion of tumor cells. This gene encodes a beta subunit. Multiple alternatively spliced transcript variants which encode different protein isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ITGB1
• BP4: Computational evidence support a benign effect (MetaRNN=0.12078372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB1	NM_002211.4	c.1534A>C	p.Met512Leu	missense_variant	12/16	ENST00000302278.8
ITGB1	NM_033668.2	c.1534A>C	p.Met512Leu	missense_variant	11/16
ITGB1	NM_133376.3	c.1534A>C	p.Met512Leu	missense_variant	12/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB1	ENST00000302278.8	c.1534A>C	p.Met512Leu	missense_variant	12/16	1	NM_002211.4	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152252 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74392

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.1534A>C (p.M512L) alteration is located in exon 11 (coding exon 11) of the ITGB1 gene. This alteration results from a A to C substitution at nucleotide position 1534, causing the methionine (M) at amino acid position 512 to be replaced by a leucine (L). 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	0.16
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	19
Dann	Benign	0.79
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D;.
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.64	N;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.18	N;N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.27
MutPred		0.28		Loss of phosphorylation at S509 (P = 0.1908);Loss of phosphorylation at S509 (P = 0.1908);Loss of phosphorylation at S509 (P = 0.1908);
MVP		0.43
MPC		0.73
ClinPred		0.68	D
GERP RS		6.1
Varity_R		0.23
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs55976044; hg19: chr10-33200988;