Genetic Variant ITGB1:c.2331+1249C>T (chr10-32907119-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002211.4(ITGB1):c.2331+1249C>T variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000838 in 1,193,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.4e-7 ( 0 hom. )

Consequence

ITGB1
NM_002211.4 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Publications

0 publications found

Variant links:

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]

ITGB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGB1	NM_002211.4 link	c.2331+1249C>T		intron_variant	Intron 15 of 15	ENST00000302278.8	NP_002202.2	P05556-1
ITGB1	NM_033668.2 link	c.2356C>T	p.Pro786Ser	missense_variant	Exon 15 of 16		NP_391988.1	P05556-5
ITGB1	NM_133376.3 link	c.2331+1249C>T		intron_variant	Intron 15 of 15		NP_596867.1	P05556-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB1	ENST00000302278.8 link	c.2331+1249C>T		intron_variant	Intron 15 of 15	1	NM_002211.4	ENSP00000303351.3		P05556-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.38e-7

AC:

AN:

1193546

Hom.:

Cov.:

AF XY:

0.00000169

AC XY:

AN XY:

592482

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25714

American (AMR)

AF:

0.00

AC:

AN:

36464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16710

East Asian (EAS)

AF:

0.00

AC:

AN:

16696

South Asian (SAS)

AF:

0.00

AC:

AN:

81124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4434

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

936540

Other (OTH)

AF:

0.0000231

AC:

AN:

43300

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2356C>T (p.P786S) alteration is located in exon 15 (coding exon 15) of the ITGB1 gene. This alteration results from a C to T substitution at nucleotide position 2356, causing the proline (P) at amino acid position 786 to be replaced by a serine (S). 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

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.15

PhyloP100

PROVEAN

Benign

0.90

REVEL

Uncertain

0.38

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.011

Polyphen

0.018

Vest4

0.84

MutPred

0.69

Gain of MoRF binding (P = 0.0668);

MVP

0.73

ClinPred

0.64

GERP RS

5.2

Mutation Taster

=81/19

polymorphism

(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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10-32907119-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over