13-101567837-C-G

Variant names:

• chr13-101567837-C-G
• rs778714637
• NM_004791.3:c.455C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004791.3(ITGBL1):​c.455C>G​(p.Ser152Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,460,432 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: 0.0000055 (0 hom.)
• Consequence: ITGBL1 NM_004791.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.09

Genes affected

ITGBL1 (HGNC:6164): (integrin subunit beta like 1) This gene encodes a beta integrin-related protein that is a member of the EGF-like protein family. The encoded protein contains integrin-like cysteine-rich repeats. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGBL1	NM_004791.3	c.455C>G	p.Ser152Cys	missense_variant	Exon 3 of 11	ENST00000376180.8	NP_004782.1
ITGBL1	NM_001271756.2	c.176C>G	p.Ser59Cys	missense_variant	Exon 2 of 10		NP_001258685.1
ITGBL1	NM_001271754.2	c.32C>G	p.Ser11Cys	missense_variant	Exon 2 of 11		NP_001258683.1
ITGBL1	NM_001271755.2	c.317-7587C>G		intron_variant	Intron 2 of 9		NP_001258684.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGBL1	ENST00000376180.8	c.455C>G	p.Ser152Cys	missense_variant	Exon 3 of 11	1	NM_004791.3	ENSP00000365351.3
ITGBL1	ENST00000618057.4	c.317-7587C>G		intron_variant	Intron 2 of 9	1		ENSP00000481484.1
ITGBL1	ENST00000376162.7	c.176C>G	p.Ser59Cys	missense_variant	Exon 2 of 10	2		ENSP00000365332.3
ITGBL1	ENST00000545560.6	c.32C>G	p.Ser11Cys	missense_variant	Exon 2 of 11	2		ENSP00000439903.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250470 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135404

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460432 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726550

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.455C>G (p.S152C) alteration is located in exon 3 (coding exon 3) of the ITGBL1 gene. This alteration results from a C to G substitution at nucleotide position 455, causing the serine (S) at amino acid position 152 to be replaced by a cysteine (C). 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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.2	D;.;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.84
MutPred		0.41		Gain of catalytic residue at N153 (P = 0);.;.;.;
MVP		0.88
MPC		0.73
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.46
gMVP		0.84

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: rs778714637; hg19: chr13-102220188;