rs149710421

Variant names:

• chr11-6609293-C-T
• rs149710421
• NM_006284.4:c.*1629G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_004517.4(ILK):​c.619-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000617 in 1,613,736 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (5 hom.)
• Consequence: ILK NM_004517.4 splice_region, intron
• Scores: Splicing: ADA: 0.0003031
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.769
• Publications: 1 publications found

Genes affected

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]

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: NO_KNOWN Submitted by: ClinGen

ENSG00000254641 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 11-6609293-C-T is Benign according to our data. Variant chr11-6609293-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 82 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004517.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF10	NM_006284.4	MANE Select	c.*1629G>A		3_prime_UTR	Exon 5 of 5	NP_006275.1	Q12962
	ILK	NM_004517.4	MANE Select	c.619-6C>T		splice_region intron	N/A	NP_004508.1	Q13418-1
	ILK	NM_001014794.3		c.619-6C>T		splice_region intron	N/A	NP_001014794.1	Q13418-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF10	ENST00000299424.9	TSL:1 MANE Select	c.*1629G>A		3_prime_UTR	Exon 5 of 5	ENSP00000299424.4	Q12962
	ILK	ENST00000299421.9	TSL:1 MANE Select	c.619-6C>T		splice_region intron	N/A	ENSP00000299421.4	Q13418-1
	ILK	ENST00000396751.6	TSL:1	c.619-6C>T		splice_region intron	N/A	ENSP00000379975.2	Q13418-1

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000859 AC: 216 AN: 251410 AF XY: 0.000971

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000809

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.000625 AC: 913 AN: 1461458 Hom.: 5 Cov.: 34 AF XY: 0.000667 AC XY: 485 AN XY: 727064

African (AFR) AF: 0.000329 AC: 11 AN: 33478

American (AMR) AF: 0.00121 AC: 54 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00132 AC: 114 AN: 86250

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53368

Middle Eastern (MID) AF: 0.0127 AC: 73 AN: 5768

European-Non Finnish (NFE) AF: 0.000487 AC: 541 AN: 1111658

Other (OTH) AF: 0.00129 AC: 78 AN: 60376

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74470

African (AFR) AF: 0.000120 AC: 5 AN: 41552

American (AMR) AF: 0.00137 AC: 21 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.000961 Hom.: 0

Bravo AF: 0.000703

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	3.4
DANN	Benign	0.80
PhyloP100		0.77
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.014
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: rs149710421; hg19: chr11-6630524;