10-90919148-G-T

Variant names:

• chr10-90919148-G-T
• rs200061926
• NM_014391.3:c.328C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014391.3(ANKRD1):​c.328C>A​(p.Pro110Thr) 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. 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. P110S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANKRD1 NM_014391.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12
• 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
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37403727).

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.328C>A	p.Pro110Thr	missense	Exon 3 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.328C>A	p.Pro110Thr	missense	Exon 3 of 9	ENSP00000360762.3	Q15327
	ANKRD1	ENST00000869698.1		c.328C>A	p.Pro110Thr	missense	Exon 3 of 8	ENSP00000539757.1
	ANKRD1	ENST00000945870.1		c.328C>A	p.Pro110Thr	missense	Exon 3 of 8	ENSP00000615929.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3 AN: 1460330 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726390

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111338

Other (OTH) AF: 0.0000166 AC: 1 AN: 60326

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

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	0.061
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.1
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.21
MutPred		0.19		Gain of phosphorylation at P110 (P = 0.0407)
MVP		0.85
MPC		0.18
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.62
gMVP		0.35
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs200061926; hg19: chr10-92678905;