NM_004517.4:c.211delC

Variant names:

• chr11-6608161-AC-A
• rs776120061
• NM_004517.4:c.211delC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004517.4(ILK):​c.211delC​(p.Leu71CysfsTer26) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ILK NM_004517.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47

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 Uncertain_significance. Variant got 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
ILK	NM_004517.4	c.211delC	p.Leu71CysfsTer26	frameshift_variant	Exon 3 of 13	ENST00000299421.9	NP_004508.1
TAF10	NM_006284.4	c.*2760delG		3_prime_UTR_variant	Exon 5 of 5	ENST00000299424.9	NP_006275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ILK	ENST00000299421.9	c.211delC	p.Leu71CysfsTer26	frameshift_variant	Exon 3 of 13	1	NM_004517.4	ENSP00000299421.4
TAF10	ENST00000299424	c.*2760delG		3_prime_UTR_variant	Exon 5 of 5	1	NM_006284.4	ENSP00000299424.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 11, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu71fs variant in ILK has been identified by our laboratory in 1 individu al with HCM and was absent from large population studies. This variant is predic ted to cause a frameshift, which alters the protein?s amino acid sequence beginn ing at position 71 and leads to a premature termination codon 26 amino acids dow nstream. This alteration is then predicted to lead to a truncated or absent prot ein. Homozygous loss of ILK function has been shown to cause DCM in animal model s (Knoll 2007, White 2006, Dai 2014); however, limited data exists to link the g ene to human cardiac disease, as only two missense variants have been reported i n 2 patients with DCM (Knoll 2007, Meder 2011), neither with sufficient evidence to prove pathogenicity. In summary, the clinical significance of the p.Leu71fs variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs776120061; hg19: chr11-6629391;