13-101575497-G-T

Variant names:

• chr13-101575497-G-T
• rs1421267796
• NM_004791.3:c.537G>T

Variant summary

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

The NM_004791.3(ITGBL1):​c.537G>T​(p.Glu179Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,614 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ITGBL1 NM_004791.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.408
• Publications: 1 publications found

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

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
ITGBL1	NM_004791.3	c.537G>T	p.Glu179Asp	missense_variant	Exon 4 of 11	ENST00000376180.8	NP_004782.1
ITGBL1	NM_001271755.2	c.390G>T	p.Glu130Asp	missense_variant	Exon 3 of 10		NP_001258684.1
ITGBL1	NM_001271756.2	c.258G>T	p.Glu86Asp	missense_variant	Exon 3 of 10		NP_001258685.1
ITGBL1	NM_001271754.2	c.114G>T	p.Glu38Asp	missense_variant	Exon 3 of 11		NP_001258683.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGBL1	ENST00000376180.8	c.537G>T	p.Glu179Asp	missense_variant	Exon 4 of 11	1	NM_004791.3	ENSP00000365351.3
ITGBL1	ENST00000618057.4	c.390G>T	p.Glu130Asp	missense_variant	Exon 3 of 10	1		ENSP00000481484.1
ITGBL1	ENST00000376162.7	c.258G>T	p.Glu86Asp	missense_variant	Exon 3 of 10	2		ENSP00000365332.3
ITGBL1	ENST00000545560.6	c.114G>T	p.Glu38Asp	missense_variant	Exon 3 of 11	2		ENSP00000439903.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251238 AF XY: 0.00000736

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000274 AC: 4 AN: 1460496 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726648

African (AFR) AF: 0.000120 AC: 4 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110964

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152118 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74318

African (AFR) AF: 0.000121 AC: 5 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.537G>T (p.E179D) alteration is located in exon 4 (coding exon 4) of the ITGBL1 gene. This alteration results from a G to T substitution at nucleotide position 537, causing the glutamic acid (E) at amino acid position 179 to be replaced by an aspartic acid (D). 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	0.66
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	T;T;T;.;.
Eigen	Benign	0.090
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.46	T;T;T;T;T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.7	.;M;.;.;.
PhyloP100		0.41
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.47	.;N;.;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.068	.;T;.;D;D
Sift4G	Uncertain	0.058	T;T;T;T;T
Polyphen		1.0	.;D;.;.;.
Vest4		0.62
MutPred		0.37		.;Gain of catalytic residue at K176 (P = 0.0082);.;.;.;
MVP		0.69
MPC		0.72
ClinPred		0.60	D
GERP RS		1.5
Varity_R		0.10
gMVP		0.59
Mutation Taster		=45/55	disease causing

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: rs1421267796; hg19: chr13-102227848;