1-28743910-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_016258.3(YTHDF2):c.1640A>G(p.Tyr547Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

YTHDF2
NM_016258.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.03

Variant links:

Genes affected

YTHDF2 (HGNC:31675): (YTH N6-methyladenosine RNA binding protein F2) This gene encodes a member of the YTH (YT521-B homology) superfamily containing YTH domain. The YTH domain is typical for the eukaryotes and is particularly abundant in plants. The YTH domain is usually located in the middle of the protein sequence and may function in binding to RNA. In addition to a YTH domain, this protein has a proline rich region which may be involved in signal transduction. An Alu-rich domain has been identified in one of the introns of this gene, which is thought to be associated with human longevity. In addition, reciprocal translocations between this gene and the Runx1 (AML1) gene on chromosome 21 has been observed in patients with acute myeloid leukemia. This gene was initially mapped to chromosome 14, which was later turned out to be a pseudogene. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. [provided by RefSeq, Oct 2012]

YTHDF2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YTHDF2	NM_016258.3 link	c.1640A>G	p.Tyr547Cys	missense_variant	Exon 4 of 5	ENST00000373812.8	NP_057342.2	Q9Y5A9-1
YTHDF2	NM_001173128.2 link	c.1640A>G	p.Tyr547Cys	missense_variant	Exon 5 of 6		NP_001166599.1	Q9Y5A9-1
YTHDF2	NM_001172828.2 link	c.1490A>G	p.Tyr497Cys	missense_variant	Exon 3 of 4		NP_001166299.1	Q9Y5A9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
YTHDF2	ENST00000373812.8 link	c.1640A>G	p.Tyr547Cys	missense_variant	Exon 4 of 5	1	NM_016258.3	ENSP00000362918.3	Q9Y5A9-1
YTHDF2	ENST00000478283.5 link	n.2321A>G		non_coding_transcript_exon_variant	Exon 3 of 4	1
YTHDF2	ENST00000542507.5 link	c.1640A>G	p.Tyr547Cys	missense_variant	Exon 5 of 6	5		ENSP00000444660.1	Q9Y5A9-1
YTHDF2	ENST00000541996.5 link	c.1490A>G	p.Tyr497Cys	missense_variant	Exon 3 of 4	2		ENSP00000439394.1	Q9Y5A9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000429

AC:

AN:

233326

Hom.:

AF XY:

0.00000784

AC XY:

AN XY:

127568

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000570

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451836

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721768

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

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.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000831

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1640A>G (p.Y547C) alteration is located in exon 4 (coding exon 4) of the YTHDF2 gene. This alteration results from a A to G substitution at nucleotide position 1640, causing the tyrosine (Y) at amino acid position 547 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;T;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

D;.;D

M_CAP

Benign

0.082

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Benign

-0.57

MutationAssessor

Pathogenic

3.4

M;M;.

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-8.1

D;D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.89

MutPred

0.70

Loss of ubiquitination at K548 (P = 0.0532);Loss of ubiquitination at K548 (P = 0.0532);.;

MVP

0.58

MPC

1.8

ClinPred

0.99

GERP RS

5.8

Varity_R

0.79

gMVP

0.80

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over