10-90919283-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014391.3(ANKRD1):c.208-15G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,594,152 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: ANKRD1 NM_014391.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.532

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 10-90919283-C-T is Benign according to our data. Variant chr10-90919283-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-90919283-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD1	NM_014391.3	c.208-15G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000371697.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD1	ENST00000371697.4	c.208-15G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014391.3	P1

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 259 AN: 151970 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00602

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000418 AC: 99 AN: 236878 Hom.: 0 AF XY: 0.000318 AC XY: 41 AN XY: 128860

Gnomad AFR exome AF: 0.00563

Gnomad AMR exome AF: 0.000179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000203

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000924

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000167 AC: 241 AN: 1442066 Hom.: 1 Cov.: 31 AF XY: 0.000150 AC XY: 108 AN XY: 717656

Gnomad4 AFR exome AF: 0.00578

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000153

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000543

Gnomad4 OTH exome AF: 0.000436

GnomAD4 genome AF: 0.00172 AC: 261 AN: 152086 Hom.: 2 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74348

Gnomad4 AFR AF: 0.00605

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000902 Hom.: 0

Bravo AF: 0.00184

Asia WGS AF: 0.00173 AC: 6 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2012	208-15G>A in Intron 02 of ANKRD1: This variant is not expected to have clinical significance because it has been identified in 0.6% (24/3726) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs116511484). 208-15G>A in Intron 02 of AN KRD1 (allele frequency = 0.6%, 24/3726; dbSNP rs116511484) ** -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2024	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

ANKRD1-related dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	8.9
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs116511484; hg19: chr10-92679040; COSMIC: COSV63310918; COSMIC: COSV63310918;