10-90918971-G-T

Variant names:

• chr10-90918971-G-T
• rs142354133
• NM_014391.3:c.347C>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.347C>A​(p.Thr116Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T116M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ANKRD1 NM_014391.3 missense, splice_region
• Scores: Splicing: ADA: 0.05518
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.37
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2334981).

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.347C>A	p.Thr116Lys	missense splice_region	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.347C>A	p.Thr116Lys	missense splice_region	Exon 4 of 9	ENSP00000360762.3	Q15327
	ANKRD1	ENST00000869698.1		c.347C>A	p.Thr116Lys	missense splice_region	Exon 4 of 8	ENSP00000539757.1
	ANKRD1	ENST00000945870.1		c.347C>A	p.Thr116Lys	missense splice_region	Exon 4 of 8	ENSP00000615929.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436374 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 715504

African (AFR) AF: 0.00 AC: 0 AN: 31166

American (AMR) AF: 0.00 AC: 0 AN: 44460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25880

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38154

South Asian (SAS) AF: 0.00 AC: 0 AN: 85426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095672

Other (OTH) AF: 0.00 AC: 0 AN: 59174

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.00052	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	29
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.4
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.14
Sift	Benign	0.51	T
Sift4G	Benign	0.75	T
Polyphen		0.18	B
Vest4		0.40
MutPred		0.33		Gain of ubiquitination at T116 (P = 0.0048)
MVP		0.82
MPC		0.24
ClinPred		0.77	D
GERP RS		5.5
Varity_R		0.21
gMVP		0.37
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.055
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.69		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142354133; hg19: chr10-92678728; COSMIC: COSV63310993; COSMIC: COSV63310993;