10-90918981-AAAATAAATAAAT-AAAATAAATAAATAAAT

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_014391.3(ANKRD1):c.346-13_346-10dupATTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,312,720 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 8 hom., cov: 18)

Exomes 𝑓: 0.000048 ( 1 hom. )

Consequence

ANKRD1
NM_014391.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.181

Publications

3 publications found

Variant links:

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]

ANKRD1 Gene-Disease associations (from GenCC):

familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ANKRD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP6

Variant 10-90918981-A-AAAAT is Benign according to our data. Variant chr10-90918981-A-AAAAT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 136 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD1	NM_014391.3 link	c.346-13_346-10dupATTT		intron_variant	Intron 3 of 8	ENST00000371697.4	NP_055206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD1	ENST00000371697.4 link	c.346-10_346-9insATTT		intron_variant	Intron 3 of 8	1	NM_014391.3	ENSP00000360762.3

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

135

AN:

91022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000113

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00235

GnomAD2 exomes

AF:

0.000367

AC:

AN:

84372

AF XY:

0.000467

show subpopulations

Gnomad AFR exome

AF:

0.00452

Gnomad AMR exome

AF:

0.000102

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000155

Gnomad NFE exome

AF:

0.000131

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000483

AC:

AN:

1221698

Hom.:

Cov.:

AF XY:

0.0000553

AC XY:

AN XY:

614710

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00214

AC:

AN:

18734

American (AMR)

AF:

0.0000503

AC:

AN:

39768

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23594

East Asian (EAS)

AF:

0.00

AC:

AN:

30678

South Asian (SAS)

AF:

0.0000274

AC:

AN:

73060

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4832

European-Non Finnish (NFE)

AF:

0.00000748

AC:

AN:

935456

Other (OTH)

AF:

0.000159

AC:

AN:

50334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000828793), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.393

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00149

AC:

136

AN:

91022

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

AN XY:

43546

show subpopulations

African (AFR)

AF:

0.00486

AC:

132

AN:

27168

American (AMR)

AF:

0.000113

AC:

AN:

8876

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2240

East Asian (EAS)

AF:

0.00

AC:

AN:

3478

South Asian (SAS)

AF:

0.00

AC:

AN:

2888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

204

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

39976

Other (OTH)

AF:

0.00235

AC:

AN:

1278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 10, 2025

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ANKRD1 c.346-13_346-10dupATTT alters a nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00015 in 1307092 control chromosomes, predominantly at a frequency of 0.0037 within the African or African-American subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 150-fold of the estimated maximal expected allele frequency for a pathogenic variant in ANKRD1 causing Cardiomyopathy phenotype (2.5e-05). To our knowledge, no occurrence of c.346-13_346-10dupATTT in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 416999). Based on the evidence outlined above, the variant was classified as benign.

ANKRD1-related dilated cardiomyopathy

Benign:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ANKRD1-related disorder

Benign:1

Apr 01, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.18

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over