rs1554827420

chr10-90912958-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014391.3(ANKRD1):c.868G>A(p.Asp290Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANKRD1 NM_014391.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD1	NM_014391.3	c.868G>A	p.Asp290Asn	missense_variant	9/9	ENST00000371697.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD1	ENST00000371697.4	c.868G>A	p.Asp290Asn	missense_variant	9/9	1	NM_014391.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461756 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

ANKRD1-related dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 28, 2022

ClinVar contains an entry for this variant (Variation ID: 477613). This variant has not been reported in the literature in individuals affected with ANKRD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 290 of the ANKRD1 protein (p.Asp290Asn). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANKRD1 protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.0092	T
BayesDel_noAF	Benign	-0.25
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		0.95	P
Vest4		0.46
MutPred		0.69		Gain of MoRF binding (P = 0.1399);
MVP		0.89
MPC		0.53
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.29
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554827420; hg19: chr10-92672715;