11-6608113-T-A

Position:

• chr11-6608113-T-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004517.4(ILK):​c.157T>A​(p.Leu53Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,614,142 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: ILK NM_004517.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.06

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]

TAF10 (HGNC:11543): (TATA-box binding protein associated factor 10) Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes one of the small subunits of TFIID that is associated with a subset of TFIID complexes. Studies with human and mammalian cells have shown that this subunit is required for transcriptional activation by the estrogen receptor, for progression through the cell cycle, and may also be required for certain cellular differentiation programs. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10162446).
• BS2: High AC in GnomAd4 at 71 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ILK	NM_004517.4	c.157T>A	p.Leu53Met	missense_variant	3/13	ENST00000299421.9
TAF10	NM_006284.4	c.*2809A>T		3_prime_UTR_variant	5/5	ENST00000299424.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ILK	ENST00000299421.9	c.157T>A	p.Leu53Met	missense_variant	3/13	1	NM_004517.4	P1
TAF10	ENST00000299424.9	c.*2809A>T		3_prime_UTR_variant	5/5	1	NM_006284.4	P1

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000382 AC: 96 AN: 251482 Hom.: 0 AF XY: 0.000383 AC XY: 52 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000226 AC: 331 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.000224 AC XY: 163 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00270

Gnomad4 NFE exome AF: 0.000152

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000466 AC: 71 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74454

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 22, 2017	The p.Leu53Met variant (rs200336608) was reported in one family investigated for dilated cardiomyopathy (DCM); however this variant did not segregate with affected individuals (Begay, 2016). This variant is listed in the Genome Aggregation Database (gnomAD) with a population frequency of 0.3 percent in the European Finnish population (identified on 82 out of 25,792 chromosomes), and has been reported to the ClinVar database as a variant of uncertain significance (Variation ID: 180371). The leucine at position 53 is highly conserved considering 13 species (Alamut v2.10) and computational analyses of the p.Leu53Met variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Leu53Met variant with certainty. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2020	This variant is associated with the following publications: (PMID: 28831623, 27662471, 27016271) -

Primary familial hypertrophic cardiomyopathy Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Blueprint Genetics	Dec 20, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 28, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;T;.;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.10	T;T;T;T;T;T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.7	H;.;H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.2	N;.;N;N;N;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.;D;D;D;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;.
Vest4		0.83
MVP		0.89
MPC		1.0
ClinPred		0.28	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs200336608; hg19: chr11-6629343;