Genetic Variant YTHDF1:p.His375Tyr (chr20-63202817-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017798.4(YTHDF1):c.1123C>T(p.His375Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00192 in 1,614,020 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 24 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 25 hom. )

Consequence

YTHDF1
NM_017798.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 6.58

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006365508).

BP6

Variant 20-63202817-G-A is Benign according to our data. Variant chr20-63202817-G-A is described in ClinVar as [Benign]. Clinvar id is 719846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1565/152384) while in subpopulation AFR AF= 0.0351 (1458/41590). AF 95% confidence interval is 0.0336. There are 24 homozygotes in gnomad4. There are 755 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YTHDF1	NM_017798.4 link	c.1123C>T	p.His375Tyr	missense_variant	Exon 4 of 5	ENST00000370339.8	NP_060268.2	Q9BYJ9-1
YTHDF1	XM_024451914.2 link	c.973C>T	p.His325Tyr	missense_variant	Exon 3 of 4		XP_024307682.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YTHDF1	ENST00000370339.8 link	c.1123C>T	p.His375Tyr	missense_variant	Exon 4 of 5	1	NM_017798.4	ENSP00000359364.3		Q9BYJ9-1
YTHDF1	ENST00000370334.4 link	c.133-6083C>T		intron_variant	Intron 3 of 3	3		ENSP00000359359.4		Q5JXC6

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1554

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0349

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00562

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00262

AC:

658

AN:

251190

Hom.:

AF XY:

0.00188

AC XY:

255

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0356

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00105

AC:

1539

AN:

1461636

Hom.:

Cov.:

AF XY:

0.000871

AC XY:

633

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.0350

Gnomad4 AMR exome

AF:

0.00183

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000102

Gnomad4 OTH exome

AF:

0.00245

GnomAD4 genome

AF:

0.0103

AC:

1565

AN:

152384

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

755

AN XY:

74526

show subpopulations

Gnomad4 AFR

AF:

0.0351

Gnomad4 AMR

AF:

0.00562

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00201

Hom.:

Bravo

AF:

0.0115

ESP6500AA

AF:

0.0329

AC:

145

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00321

AC:

390

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0064

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.20

Sift

Uncertain

0.0010

Sift4G

Benign

0.063

Polyphen

0.68

Vest4

0.64

MVP

0.043

MPC

1.2

ClinPred

0.031

GERP RS

4.7

Varity_R

0.75

gMVP

0.66

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