NM_014391.3:c.820T>C

Variant names:

• chr10-90915572-A-G
• rs377074932
• NM_014391.3:c.820T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_014391.3(ANKRD1):​c.820T>C​(p.Tyr274His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,613,968 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y274D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: ANKRD1 NM_014391.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 3.51
• Publications: 2 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1182656).
• BP6: Variant 10-90915572-A-G is Benign according to our data. Variant chr10-90915572-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180276.
• BS2: High AC in GnomAd4 at 10 AD gene.

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.820T>C	p.Tyr274His	missense	Exon 8 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.820T>C	p.Tyr274His	missense	Exon 8 of 9	ENSP00000360762.3	Q15327
	ANKRD1	ENST00000869698.1		c.721T>C	p.Tyr241His	missense	Exon 7 of 8	ENSP00000539757.1
	ANKRD1	ENST00000945870.1		c.721T>C	p.Tyr241His	missense	Exon 7 of 8	ENSP00000615929.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152182 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000996 AC: 25 AN: 251076 AF XY: 0.0000958

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000740

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000135 AC: 198 AN: 1461786 Hom.: 1 Cov.: 32 AF XY: 0.000135 AC XY: 98 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.000618 AC: 33 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000142 AC: 158 AN: 1111966

Other (OTH) AF: 0.0000828 AC: 5 AN: 60388

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152182 Hom.: 0 Cov.: 30 AF XY: 0.0000538 AC XY: 4 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000376 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	ANKRD1-related dilated cardiomyopathy (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not provided (1)
-	-	1	not specified (1)
-	1	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.050	N
PhyloP100		3.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.095
Sift	Benign	0.39	T
Sift4G	Benign	0.67	T
Polyphen		0.0010	B
Vest4		0.39
MVP		0.73
MPC		0.21
ClinPred		0.10	T
GERP RS		4.4
Varity_R		0.089
gMVP		0.60
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs377074932; hg19: chr10-92675329;