10-90918981-AAAATAAATAAAT-AAAATAAAT

Variant names:

• chr10-90918981-AAAAT-A
• rs397517250
• NM_014391.3:c.346-13_346-10delATTT

Variant summary

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

The NM_014391.3(ANKRD1):​c.346-13_346-10delATTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,221,686 control chromosomes in the GnomAD database, including 1 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), 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 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000020 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANKRD1 NM_014391.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.67
• 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-AAAAT-A is Benign according to our data. Variant chr10-90918981-AAAAT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201658.

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.346-13_346-10delATTT		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.346-13_346-10delATTT		intron	N/A	ENSP00000360762.3	Q15327
	ANKRD1	ENST00000869698.1		c.346-13_346-10delATTT		intron	N/A	ENSP00000539757.1
	ANKRD1	ENST00000945870.1		c.346-13_346-10delATTT		intron	N/A	ENSP00000615929.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 91026 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.0000948 AC: 8 AN: 84372 AF XY: 0.000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000157

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 25 AN: 1221686 Hom.: 1 AF XY: 0.0000277 AC XY: 17 AN XY: 614702

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

African (AFR) AF: 0.00 AC: 0 AN: 18760

American (AMR) AF: 0.00 AC: 0 AN: 39774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23594

East Asian (EAS) AF: 0.0000326 AC: 1 AN: 30674

South Asian (SAS) AF: 0.0000274 AC: 2 AN: 73062

European-Finnish (FIN) AF: 0.0000221 AC: 1 AN: 45242

Middle Eastern (MID) AF: 0.000207 AC: 1 AN: 4832

European-Non Finnish (NFE) AF: 0.0000214 AC: 20 AN: 935418

Other (OTH) AF: 0.00 AC: 0 AN: 50330

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000523248), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 91026 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 43532

African (AFR) AF: 0.00 AC: 0 AN: 27142

American (AMR) AF: 0.00 AC: 0 AN: 8878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2240

East Asian (EAS) AF: 0.00 AC: 0 AN: 3488

South Asian (SAS) AF: 0.00 AC: 0 AN: 2892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 224

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 39974

Other (OTH) AF: 0.00 AC: 0 AN: 1274

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	ANKRD1-related dilated cardiomyopathy (1)
-	-	1	Cardiomyopathy (1)
-	1	-	Dilated Cardiomyopathy, Dominant (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs397517250; hg19: chr10-92678738;