rs28730751

Variant names:

• chr10-90920228-C-A
• rs28730751
• NM_014391.3:c.148G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-90920228-C-A
• chr10-90920228-C-G
• chr10-90920228-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014391.3(ANKRD1):​c.148G>T​(p.Ala50Ser) 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. 17/22 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. A50P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANKRD1 NM_014391.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.510
• 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
• dilated cardiomyopathy

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06304464).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD1	NM_014391.3	c.148G>T	p.Ala50Ser	missense_variant	Exon 2 of 9	ENST00000371697.4	NP_055206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD1	ENST00000371697.4	c.148G>T	p.Ala50Ser	missense_variant	Exon 2 of 9	1	NM_014391.3	ENSP00000360762.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Oct 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A50S variant (also known as c.148G>T), located in coding exon 2 of the ANKRD1 gene, results from a G to T substitution at nucleotide position 148. The alanine at codon 50 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.2
DANN	Benign	0.71
DEOGEN2	Benign	0.075	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.51
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.054
Sift	Benign	0.72	T
Sift4G	Benign	0.72	T
Polyphen		0.0030	B
Vest4		0.21
MutPred		0.21		Gain of ubiquitination at K46 (P = 0.0545);
MVP		0.68
MPC		0.15
ClinPred		0.018	T
GERP RS		0.18
Varity_R		0.075
gMVP		0.12
Mutation Taster		=98/2	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: rs28730751; hg19: chr10-92679985;