Genetic Variant ITGBL1:p.Asp456Tyr (chr13-101714524-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_004791.3(ITGBL1):c.1366G>T(p.Asp456Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D456N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ITGBL1
NM_004791.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.60

Publications

2 publications found

Variant links:

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]

ITGBL1 links:

FGF14 (HGNC:3671): (fibroblast growth factor 14) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. A mutation in this gene is associated with autosomal dominant cerebral ataxia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

FGF14 Gene-Disease associations (from GenCC):

spinocerebellar ataxia 27A
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
spinocerebellar ataxia type 27
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
autosomal recessive cerebellar ataxia
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

FGF14 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGBL1	NM_004791.3 link	c.1366G>T	p.Asp456Tyr	missense_variant	Exon 10 of 11	ENST00000376180.8	NP_004782.1	O95965-1A0A024RDW7
FGF14	NM_004115.4 link	c.*8307C>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000376143.5	NP_004106.1	Q92915-1A0A7U3JVZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGBL1	ENST00000376180.8 link	c.1366G>T	p.Asp456Tyr	missense_variant	Exon 10 of 11	1	NM_004791.3	ENSP00000365351.3		O95965-1
FGF14	ENST00000376143.5 link	c.*8307C>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_004115.4	ENSP00000365313.4		Q92915-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1454982

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724380

African (AFR)

AF:

0.00

AC:

AN:

33312

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105796

Other (OTH)

AF:

0.00

AC:

AN:

60184

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

T;T;T;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Uncertain

0.093

MetaRNN

Pathogenic

0.78

D;D;D;D;D

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.7

.;L;.;.;.

PhyloP100

9.6

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.64

.;N;.;N;N

REVEL

Uncertain

0.50

Sift

Uncertain

0.023

.;D;.;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;D

Polyphen

1.0

.;D;.;.;.

Vest4

0.76

MutPred

0.52

.;Gain of catalytic residue at D459 (P = 0.0025);.;.;.;

MVP

0.79

MPC

0.87

ClinPred

0.87

GERP RS

6.0

Varity_R

0.20

gMVP

0.81

Mutation Taster

=18/82

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over