Genetic Variant NM_014391.3:c.347C>A (chr10-90918971-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4_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. 15/25 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 Likely pathogenic.

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

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-90918971-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.2334981).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD1	NM_014391.3 link	c.347C>A	p.Thr116Lys	missense_variant, splice_region_variant	Exon 4 of 9	ENST00000371697.4	NP_055206.2	Q15327A0A384NYH5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD1	ENST00000371697.4 link	c.347C>A	p.Thr116Lys	missense_variant, splice_region_variant	Exon 4 of 9	1	NM_014391.3	ENSP00000360762.3		Q15327

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1436374

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715504

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000262

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.00052

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Benign

0.10

Eigen

Benign

-0.14

Eigen_PC

Benign

0.078

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.79

M_CAP

Benign

0.016

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.2

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.8

REVEL

Benign

0.14

Sift

Benign

0.51

Sift4G

Benign

0.75

Polyphen

0.18

Vest4

0.40

MutPred

0.33

Gain of ubiquitination at T116 (P = 0.0048);

MVP

0.82

MPC

0.24

ClinPred

0.77

GERP RS

5.5

Varity_R

0.21

gMVP

0.37

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over