rs144770680
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_014391.3(ANKRD1):āc.838A>Gā(p.Ile280Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I280N) has been classified as Uncertain significance.
Frequency
Consequence
NM_014391.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANKRD1 | NM_014391.3 | c.838A>G | p.Ile280Val | missense_variant | 8/9 | ENST00000371697.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANKRD1 | ENST00000371697.4 | c.838A>G | p.Ile280Val | missense_variant | 8/9 | 1 | NM_014391.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152198Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251036Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135680
GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461640Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 49AN XY: 727142
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152198Hom.: 0 Cov.: 30 AF XY: 0.0000403 AC XY: 3AN XY: 74360
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 05, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 02, 2023 | Reported in association with cardiomyopathy (Arimura et al., 2009; Mazzarotto et al., 2020); however, specific clinical information was not provided; Expression of I280V in COS-7 cells revealed this variant increased binding to titin/connectin and myopalladin and altered protein localization in cardiomyocytes (Arimura et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19608032, 23299917, 19608031, 31983221, 23572067, 34400558, 28082330) - |
ANKRD1-related dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 280 of the ANKRD1 protein (p.Ile280Val). This variant is present in population databases (rs144770680, gnomAD 0.007%). This missense change has been observed in individual(s) with ANKRD1-related conditions (PMID: 19608031, 31983221). ClinVar contains an entry for this variant (Variation ID: 162746). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ANKRD1 function (PMID: 19608031, 23572067). 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. - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Mar 16, 2021 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 05, 2013 | Ile280Val in exon 8 of ANKRD1: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, the variant amino acid, valine (Val), has been identified in 7 other mammals (lemur, rat, mouse, horse, cow, alpaca, and opossum) despite high nearby amino acid conservation. In addition, computational analyses (AlignGVGD, PolyPhen2, SI FT) do not suggest a high likelihood of impact to the protein. Finally, it has b een identified in 3/8600 European American chromosomes from a broad population b y the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP r s144770680). Ile280Val in exon 8 of ANKRD1 (rs144770680; allele frequency = 3/8 600) ** - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at