Genetic Variant ITGBL1:p.Lys199Arg (chr13-101579296-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_004791.3(ITGBL1):c.596A>G(p.Lys199Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,360 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K199N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ITGBL1
NM_004791.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.87

Publications

0 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:

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ACMG classification

Classification was made for transcript

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 link	c.596A>G	p.Lys199Arg	missense_variant	Exon 5 of 11	ENST00000376180.8	NP_004782.1	O95965-1A0A024RDW7
ITGBL1	NM_001271755.2 link	c.449A>G	p.Lys150Arg	missense_variant	Exon 4 of 10		NP_001258684.1	O95965A0A087WY35
ITGBL1	NM_001271756.2 link	c.317A>G	p.Lys106Arg	missense_variant	Exon 4 of 10		NP_001258685.1	O95965-3
ITGBL1	NM_001271754.2 link	c.173A>G	p.Lys58Arg	missense_variant	Exon 4 of 11		NP_001258683.1	O95965-2B4DN32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITGBL1	ENST00000376180.8 link	c.596A>G	p.Lys199Arg	missense_variant	Exon 5 of 11	1	NM_004791.3	ENSP00000365351.3	O95965-1
ITGBL1	ENST00000618057.4 link	c.449A>G	p.Lys150Arg	missense_variant	Exon 4 of 10	1		ENSP00000481484.1	A0A087WY35
ITGBL1	ENST00000376162.7 link	c.317A>G	p.Lys106Arg	missense_variant	Exon 4 of 10	2		ENSP00000365332.3	O95965-3
ITGBL1	ENST00000545560.6 link	c.173A>G	p.Lys58Arg	missense_variant	Exon 4 of 11	2		ENSP00000439903.1	O95965-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461360

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726980

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111672

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.596A>G (p.K199R) alteration is located in exon 5 (coding exon 5) of the ITGBL1 gene. This alteration results from a A to G substitution at nucleotide position 596, causing the lysine (K) at amino acid position 199 to be replaced by an arginine (R). 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

0.097

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0068

T;T;T;.;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.60

T;T;T;D;T

M_CAP

Benign

0.068

MetaRNN

Uncertain

0.45

T;T;T;T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

0.93

.;L;.;.;.

PhyloP100

8.9

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.45

.;N;.;N;N

REVEL

Uncertain

0.59

Sift

Benign

0.054

.;T;.;T;T

Sift4G

Benign

0.35

T;T;T;T;T

Polyphen

0.63

.;P;.;.;.

Vest4

0.49

MutPred

0.48

.;Gain of catalytic residue at N204 (P = 0);.;.;.;

MVP

0.70

MPC

0.57

ClinPred

0.90

GERP RS

5.3

Varity_R

0.13

gMVP

0.43

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over