10-90918950-G-T

Variant names:

• chr10-90918950-G-T
• rs145387010
• NM_014391.3:c.368C>A

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.368C>A​(p.Thr123Lys) 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. T123M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ANKRD1 NM_014391.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.335
• Publications: 23 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
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• 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=0.19496888).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014391.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD1	NM_014391.3	MANE Select	c.368C>A	p.Thr123Lys	missense	Exon 4 of 9	NP_055206.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD1	ENST00000371697.4	TSL:1 MANE Select	c.368C>A	p.Thr123Lys	missense	Exon 4 of 9	ENSP00000360762.3	Q15327
	ANKRD1	ENST00000869698.1		c.368C>A	p.Thr123Lys	missense	Exon 4 of 8	ENSP00000539757.1
	ANKRD1	ENST00000945870.1		c.368C>A	p.Thr123Lys	missense	Exon 4 of 8	ENSP00000615929.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	ANKRD1-related dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.28
DANN	Benign	0.65
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.34
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.10
Sift	Benign	0.93	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.54
MutPred		0.35		Gain of methylation at T123 (P = 0.0206)
MVP		0.39
MPC		0.20
ClinPred		0.053	T
GERP RS		-2.3
Varity_R		0.037
gMVP		0.28
Mutation Taster		=93/7	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: rs145387010; hg19: chr10-92678707;