NM_004517.4:c.46G>T

Variant names:

• chr11-6604317-G-T
• rs1433310238
• NM_004517.4:c.46G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004517.4(ILK):​c.46G>T​(p.Val16Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V16V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ILK NM_004517.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.05
• Publications: 0 publications found

Genes affected

ILK (HGNC:6040): (integrin linked kinase) This gene encodes a protein with a kinase-like domain and four ankyrin-like repeats. The encoded protein associates at the cell membrane with the cytoplasmic domain of beta integrins, where it regulates integrin-mediated signal transduction. Activity of this protein is important in the epithelial to mesenchymal transition, and over-expression of this gene is implicated in tumor growth and metastasis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]

ILK Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000254400 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ILK	NM_004517.4	c.46G>T	p.Val16Phe	missense_variant	Exon 2 of 13	ENST00000299421.9	NP_004508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ILK	ENST00000299421.9	c.46G>T	p.Val16Phe	missense_variant	Exon 2 of 13	1	NM_004517.4	ENSP00000299421.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000812 AC: 2 AN: 246424 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.000166

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460486 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726410

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.0000448 AC: 2 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 85988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111600

Other (OTH) AF: 0.00 AC: 0 AN: 60334

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46G>T (p.V16F) alteration is located in exon 2 (coding exon 1) of the ILK gene. This alteration results from a G to T substitution at nucleotide position 46, causing the valine (V) at amino acid position 16 to be replaced by a phenylalanine (F). 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	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;T;.;T;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	.;D;.;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	1.6	L;.;L;L;L;.;.
PhyloP100		9.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.9	D;.;D;D;D;.;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0030	D;.;D;D;D;.;.
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;.;.
Vest4		0.87
MutPred		0.57		Gain of catalytic residue at R17 (P = 0.219);Gain of catalytic residue at R17 (P = 0.219);Gain of catalytic residue at R17 (P = 0.219);Gain of catalytic residue at R17 (P = 0.219);Gain of catalytic residue at R17 (P = 0.219);Gain of catalytic residue at R17 (P = 0.219);.;
MVP		0.95
MPC		1.2
ClinPred		0.98	D
GERP RS		5.0
PromoterAI		-0.0076	Neutral
Varity_R		0.90
gMVP		0.92
Mutation Taster		=13/87	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: rs1433310238; hg19: chr11-6625547;