10-90918954-G-A

Variant names:

• chr10-90918954-G-A
• rs756392442
• NM_014391.3:c.364C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014391.3(ANKRD1):​c.364C>T​(p.Pro122Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P122A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ANKRD1 NM_014391.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87
• Publications: 0 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
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19957626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD1	NM_014391.3	c.364C>T	p.Pro122Ser	missense_variant	Exon 4 of 9	ENST00000371697.4	NP_055206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD1	ENST00000371697.4	c.364C>T	p.Pro122Ser	missense_variant	Exon 4 of 9	1	NM_014391.3	ENSP00000360762.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

ANKRD1-related dilated cardiomyopathy Uncertain:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 122 of the ANKRD1 protein (p.Pro122Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ANKRD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1976862). 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%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.063
Sift	Benign	0.33	T
Sift4G	Benign	0.14	T
Polyphen		0.091	B
Vest4		0.38
MutPred		0.32		Gain of glycosylation at P122 (P = 0.0548);
MVP		0.83
MPC		0.31
ClinPred		0.38	T
GERP RS		4.7
Varity_R		0.043
gMVP		0.19
Mutation Taster		=92/8	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: rs756392442; hg19: chr10-92678711;