Genetic Variant YTHDF1:p.Val354Leu (chr20-63202880-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017798.4(YTHDF1):c.1060G>C(p.Val354Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. V354I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

YTHDF1
NM_017798.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.818

Publications

0 publications found

Variant links:

Genes affected

YTHDF1 (HGNC:15867): (YTH N6-methyladenosine RNA binding protein F1) Enables N6-methyladenosine-containing RNA binding activity and ribosome binding activity. Involved in mRNA destabilization; positive regulation of translational initiation; and stress granule assembly. Located in P-body and cytoplasmic stress granule. [provided by Alliance of Genome Resources, Apr 2022]

YTHDF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030792862).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017798.4. 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
	YTHDF1	NM_017798.4	MANE Select	c.1060G>C	p.Val354Leu	missense	Exon 4 of 5	NP_060268.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
YTHDF1	ENST00000370339.8	TSL:1 MANE Select	c.1060G>C	p.Val354Leu	missense	Exon 4 of 5	ENSP00000359364.3	Q9BYJ9-1
YTHDF1	ENST00000960125.1		c.1093G>C	p.Val365Leu	missense	Exon 4 of 5	ENSP00000630184.1
YTHDF1	ENST00000370334.4	TSL:3	c.133-6146G>C		intron	N/A	ENSP00000359359.4	Q5JXC6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251170

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461536

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0010

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.018

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.80

M_CAP

Benign

0.0061

MetaRNN

Benign

0.031

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-0.82

PrimateAI

Benign

0.30

PROVEAN

Benign

0.070

REVEL

Benign

0.0030

Sift

Benign

0.79

Sift4G

Benign

0.37

Polyphen

0.0

Vest4

0.027

MutPred

0.23

Gain of glycosylation at P351 (P = 0.1419)

MVP

0.068

MPC

0.41

ClinPred

0.016

GERP RS

-6.4

Varity_R

0.018

gMVP

0.11

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over