rs137914723

Variant names:

• chr10-90918970-C-T
• rs137914723
• NM_014391.3:c.348G>A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_014391.3(ANKRD1):​c.348G>A​(p.Thr116Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00379 in 1,564,118 control chromosomes in the GnomAD database, including 356 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (40 hom., cov: 29)
  • Exomes 𝑓: 0.0034 (316 hom.)
• Consequence: ANKRD1 NM_014391.3 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.186

Genes affected

ANKRD1 (HGNC:15819): (ankyrin repeat domain 1) The protein encoded by this gene is localized to the nucleus of endothelial cells and is induced by IL-1 and TNF-alpha stimulation. Studies in rat cardiomyocytes suggest that this gene functions as a transcription factor. Interactions between this protein and the sarcomeric proteins myopalladin and titin suggest that it may also be involved in the myofibrillar stretch-sensor system. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 10-90918970-C-T is Benign according to our data. Variant chr10-90918970-C-T is described in ClinVar as [Benign]. Clinvar id is 45633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-90918970-C-T is described in Lovd as [Benign]. Variant chr10-90918970-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.059 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD1	NM_014391.3	c.348G>A	p.Thr116Thr	splice_region_variant, synonymous_variant	Exon 4 of 9	ENST00000371697.4	NP_055206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD1	ENST00000371697.4	c.348G>A	p.Thr116Thr	splice_region_variant, synonymous_variant	Exon 4 of 9	1	NM_014391.3	ENSP00000360762.3

Frequencies

GnomAD3 genomes AF: 0.00771 AC: 1026 AN: 133122 Hom.: 39 Cov.: 29

Gnomad AFR AF: 0.00231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0622

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0124

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000185

Gnomad OTH AF: 0.0165

GnomAD3 exomes AF: 0.0146 AC: 3526 AN: 240686 Hom.: 270 AF XY: 0.0108 AC XY: 1413 AN XY: 130932

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.0979

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0106

Gnomad SAS exome AF: 0.000297

Gnomad FIN exome AF: 0.000112

Gnomad NFE exome AF: 0.000145

Gnomad OTH exome AF: 0.00973

GnomAD4 exome AF: 0.00342 AC: 4896 AN: 1430932 Hom.: 316 Cov.: 30 AF XY: 0.00286 AC XY: 2039 AN XY: 713034

Gnomad4 AFR exome AF: 0.00133

Gnomad4 AMR exome AF: 0.0939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0141

Gnomad4 SAS exome AF: 0.000293

Gnomad4 FIN exome AF: 0.0000592

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.00309

GnomAD4 genome AF: 0.00775 AC: 1032 AN: 133186 Hom.: 40 Cov.: 29 AF XY: 0.00851 AC XY: 551 AN XY: 64736

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.0625

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0127

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000185

Gnomad4 OTH AF: 0.0164

Alfa AF: 0.00295 Hom.: 1

Bravo AF: 0.0129

Asia WGS AF: 0.00665 AC: 23 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jul 07, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr116Thr in exon 4 of ANKRD1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 11.6% (1317/11318 ) of Latino chromosomes including 90 homozygotes and 1.3% (110/8288) of East Asi an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org/; dbSNP rs137914723). -

Oct 08, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Jul 31, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The ANKRD1 c.348G>A (p.Thr116Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a polymorphism outcome for this variant. 3/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant affects binding of multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1468/117822 control chromosomes (91 homozygotes) from ExAC, predominantly observed in the Latino subpopulation at a frequency of 0.116363 (1317/11318). This frequency is about 3385 times the estimated maximal expected allele frequency of a pathogenic ANKRD1 variant (0.0000344), thus this is a common benign polymorphism found primarily in the populations of Latino origin. In addition, multiple clinical diagnostic laboratories (via ClinVar) have classified this variant as benign/likely benign. This variant was also reported as a polymorphism in the literature (Arimura _2009). Taken together, this variant is classified as benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Nov 19, 2015

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ANKRD1-related dilated cardiomyopathy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype Benign:1

Aug 28, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.56		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137914723; hg19: chr10-92678727; COSMIC: COSV100792294; COSMIC: COSV100792294;