chr13-101453978-G-A

Variant names:

• chr13-101453978-G-A
• rs775199348
• NM_004791.3:c.194G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004791.3(ITGBL1):​c.194G>A​(p.Gly65Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000176 in 1,535,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: ITGBL1 NM_004791.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.300184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGBL1	NM_004791.3	c.194G>A	p.Gly65Asp	missense_variant	Exon 2 of 11	ENST00000376180.8	NP_004782.1
ITGBL1	NM_001271755.2	c.194G>A	p.Gly65Asp	missense_variant	Exon 2 of 10		NP_001258684.1
ITGBL1	NM_001271754.2	c.-108+1047G>A		intron_variant	Intron 1 of 10		NP_001258683.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGBL1	ENST00000376180.8	c.194G>A	p.Gly65Asp	missense_variant	Exon 2 of 11	1	NM_004791.3	ENSP00000365351.3
ITGBL1	ENST00000618057.4	c.194G>A	p.Gly65Asp	missense_variant	Exon 2 of 10	1		ENSP00000481484.1
ITGBL1	ENST00000545560.6	c.-108+1047G>A		intron_variant	Intron 1 of 10	2		ENSP00000439903.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000695 AC: 1 AN: 143942 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 24 AN: 1383812 Hom.: 0 Cov.: 33 AF XY: 0.0000146 AC XY: 10 AN XY: 683160

African (AFR) AF: 0.00 AC: 0 AN: 30296

American (AMR) AF: 0.00 AC: 0 AN: 34234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24640

East Asian (EAS) AF: 0.00 AC: 0 AN: 34532

South Asian (SAS) AF: 0.00 AC: 0 AN: 76938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5554

European-Non Finnish (NFE) AF: 0.0000215 AC: 23 AN: 1071590

Other (OTH) AF: 0.0000175 AC: 1 AN: 57194

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74302

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000881 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.194G>A (p.G65D) alteration is located in exon 2 (coding exon 2) of the ITGBL1 gene. This alteration results from a G to A substitution at nucleotide position 194, causing the glycine (G) at amino acid position 65 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	Benign	0.18
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.072	T;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.47	T;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.2	.;M
PhyloP100		6.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.2	.;D
REVEL	Uncertain	0.57
Sift	Benign	0.20	.;T
Sift4G	Benign	0.18	T;T
Polyphen		0.19	.;B
Vest4		0.34
MutPred		0.57		Gain of catalytic residue at G65 (P = 0);Gain of catalytic residue at G65 (P = 0);
MVP		0.60
MPC		0.27
ClinPred		0.79	D
GERP RS		5.0
Varity_R		0.38
gMVP		0.73
Mutation Taster		=79/21	polymorphism

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: rs775199348; hg19: chr13-102106329;