10-90918981-AAAATAAATAAAT-AAAATAAATAAATAAAT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.181
• 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: 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.

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_346-10dupATTT		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.346-10_346-9insATTT		intron	N/A	ENSP00000360762.3	Q15327
	ANKRD1	ENST00000869698.1		c.346-10_346-9insATTT		intron	N/A	ENSP00000539757.1
	ANKRD1	ENST00000945870.1		c.346-10_346-9insATTT		intron	N/A	ENSP00000615929.1

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 135 AN: 91022 Hom.: 8 Cov.: 18

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: 31 AN: 84372 AF XY: 0.000467

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: 59 AN: 1221698 Hom.: 1 Cov.: 26 AF XY: 0.0000553 AC XY: 34 AN XY: 614710

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

African (AFR) AF: 0.00214 AC: 40 AN: 18734

American (AMR) AF: 0.0000503 AC: 2 AN: 39768

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30678

South Asian (SAS) AF: 0.0000274 AC: 2 AN: 73060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4832

European-Non Finnish (NFE) AF: 0.00000748 AC: 7 AN: 935456

Other (OTH) AF: 0.000159 AC: 8 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.

GnomAD4 genome AF: 0.00149 AC: 136 AN: 91022 Hom.: 8 Cov.: 18 AF XY: 0.00131 AC XY: 57 AN XY: 43546

African (AFR) AF: 0.00486 AC: 132 AN: 27168

American (AMR) AF: 0.000113 AC: 1 AN: 8876

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3478

South Asian (SAS) AF: 0.00 AC: 0 AN: 2888

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 204

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 39976

Other (OTH) AF: 0.00235 AC: 3 AN: 1278

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	ANKRD1-related dilated cardiomyopathy (1)
-	-	1	ANKRD1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.18

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;