13-101567770-A-G

Variant names:

• chr13-101567770-A-G
• rs199728594
• NM_004791.3:c.388A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004791.3(ITGBL1):​c.388A>G​(p.Thr130Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,613,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ITGBL1 NM_004791.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03496903).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGBL1	NM_004791.3	c.388A>G	p.Thr130Ala	missense_variant	Exon 3 of 11	ENST00000376180.8	NP_004782.1
ITGBL1	NM_001271756.2	c.109A>G	p.Thr37Ala	missense_variant	Exon 2 of 10		NP_001258685.1
ITGBL1	NM_001271754.2	c.-36A>G		5_prime_UTR_variant	Exon 2 of 11		NP_001258683.1
ITGBL1	NM_001271755.2	c.317-7654A>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.388A>G	p.Thr130Ala	missense_variant	Exon 3 of 11	1	NM_004791.3	ENSP00000365351.3
ITGBL1	ENST00000618057.4	c.317-7654A>G		intron_variant	Intron 2 of 9	1		ENSP00000481484.1
ITGBL1	ENST00000376162.7	c.109A>G	p.Thr37Ala	missense_variant	Exon 2 of 10	2		ENSP00000365332.3
ITGBL1	ENST00000545560.6	c.-36A>G		5_prime_UTR_variant	Exon 2 of 11	2		ENSP00000439903.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

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: 0.000479

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 251158 AF XY: 0.0000221

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461040 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12 AN XY: 726872

African (AFR) AF: 0.000419 AC: 14 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111406

Other (OTH) AF: 0.0000497 AC: 3 AN: 60342

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74486

African (AFR) AF: 0.000529 AC: 22 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15288

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: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000588 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.388A>G (p.T130A) alteration is located in exon 3 (coding exon 3) of the ITGBL1 gene. This alteration results from a A to G substitution at nucleotide position 388, causing the threonine (T) at amino acid position 130 to be replaced by an alanine (A). 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	0.069
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Benign	0.83
DEOGEN2	Benign	0.019	T;T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.53	T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.035	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.41	N;.;.
PhyloP100		1.7
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.70	N;.;N
REVEL	Benign	0.088
Sift	Benign	0.18	T;.;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.16
MVP		0.47
MPC		0.20
ClinPred		0.010	T
GERP RS		1.4
Varity_R		0.034
gMVP		0.51
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199728594; hg19: chr13-102220121; COSMIC: COSV104690833;