10-90918981-AAAATAAAT-A

Variant names:

• chr10-90918981-AAAATAAAT-A
• rs397517250
• NM_014391.3:c.346-17_346-10delATTTATTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_014391.3(ANKRD1):​c.346-17_346-10delATTTATTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,269,304 control chromosomes in the GnomAD database, including 3,441 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0059 (7 hom., cov: 0)
  • Exomes 𝑓: 0.020 (3434 hom.)
• Consequence: ANKRD1 NM_014391.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.19
• Publications: 3 publications found

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
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 10-90918981-AAAATAAAT-A is Benign according to our data. Variant chr10-90918981-AAAATAAAT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45631.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014391.3. 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
	ANKRD1	NM_014391.3	MANE Select	c.346-17_346-10delATTTATTT		intron	N/A	NP_055206.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD1	ENST00000371697.4	TSL:1 MANE Select	c.346-17_346-10delATTTATTT		intron	N/A	ENSP00000360762.3	Q15327
	ANKRD1	ENST00000869698.1		c.346-17_346-10delATTTATTT		intron	N/A	ENSP00000539757.1
	ANKRD1	ENST00000945870.1		c.346-17_346-10delATTTATTT		intron	N/A	ENSP00000615929.1

Frequencies

GnomAD3 genomes AF: 0.00587 AC: 524 AN: 89238 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.00598

Gnomad AMI AF: 0.00169

Gnomad AMR AF: 0.00343

Gnomad ASJ AF: 0.00316

Gnomad EAS AF: 0.00588

Gnomad SAS AF: 0.00566

Gnomad FIN AF: 0.00638

Gnomad MID AF: 0.00459

Gnomad NFE AF: 0.00666

Gnomad OTH AF: 0.00158

GnomAD2 exomes AF: 0.127 AC: 10740 AN: 84372 AF XY: 0.119

Gnomad AFR exome AF: 0.410

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.0573

Gnomad EAS exome AF: 0.221

Gnomad FIN exome AF: 0.0706

Gnomad NFE exome AF: 0.0675

Gnomad OTH exome AF: 0.0980

GnomAD4 exome AF: 0.0199 AC: 23458 AN: 1180070 Hom.: 3434 AF XY: 0.0206 AC XY: 12232 AN XY: 592942

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

African (AFR) AF: 0.134 AC: 2270 AN: 16922

American (AMR) AF: 0.0713 AC: 2592 AN: 36358

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 416 AN: 22630

East Asian (EAS) AF: 0.0619 AC: 1746 AN: 28212

South Asian (SAS) AF: 0.0519 AC: 3518 AN: 67806

European-Finnish (FIN) AF: 0.0178 AC: 778 AN: 43668

Middle Eastern (MID) AF: 0.0225 AC: 105 AN: 4662

European-Non Finnish (NFE) AF: 0.0121 AC: 10989 AN: 911588

Other (OTH) AF: 0.0216 AC: 1044 AN: 48224

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00588 AC: 525 AN: 89234 Hom.: 7 Cov.: 0 AF XY: 0.00604 AC XY: 258 AN XY: 42742

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

African (AFR) AF: 0.00598 AC: 159 AN: 26608

American (AMR) AF: 0.00343 AC: 30 AN: 8746

Ashkenazi Jewish (ASJ) AF: 0.00316 AC: 7 AN: 2218

East Asian (EAS) AF: 0.00619 AC: 21 AN: 3390

South Asian (SAS) AF: 0.00567 AC: 16 AN: 2820

European-Finnish (FIN) AF: 0.00638 AC: 27 AN: 4230

Middle Eastern (MID) AF: 0.00505 AC: 1 AN: 198

European-Non Finnish (NFE) AF: 0.00666 AC: 261 AN: 39168

Other (OTH) AF: 0.00158 AC: 2 AN: 1266

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Congenital total pulmonary venous return anomaly (3)
-	-	3	not specified (3)
-	-	1	ANKRD1-related dilated cardiomyopathy (1)
-	-	1	Cardiomyopathy (1)
-	1	-	Dilated Cardiomyopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs397517250; hg19: chr10-92678738;