Genetic Variant YTHDF1:p.Asn497Asn (chr20-63202449-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_017798.4(YTHDF1):c.1491C>T(p.Asn497Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,614,264 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 12 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 13 hom. )

Consequence

YTHDF1
NM_017798.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0990

Publications

1 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 20-63202449-G-A is Benign according to our data. Variant chr20-63202449-G-A is described in ClinVar as Benign. ClinVar VariationId is 720603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.099 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00733 (1117/152370) while in subpopulation AFR AF = 0.0243 (1010/41572). AF 95% confidence interval is 0.0231. There are 12 homozygotes in GnomAd4. There are 516 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

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.1491C>T	p.Asn497Asn	synonymous	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.1491C>T	p.Asn497Asn	synonymous	Exon 4 of 5	ENSP00000359364.3	Q9BYJ9-1
YTHDF1	ENST00000960125.1		c.1524C>T	p.Asn508Asn	synonymous	Exon 4 of 5	ENSP00000630184.1
YTHDF1	ENST00000370334.4	TSL:3	c.133-5715C>T		intron	N/A	ENSP00000359359.4	Q5JXC6

Frequencies

GnomAD3 genomes

AF:

0.00722

AC:

1100

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0240

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00250

AC:

629

AN:

251478

AF XY:

0.00211

show subpopulations

Gnomad AFR exome

AF:

0.0252

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.00863

Gnomad EAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.000316

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00104

AC:

1519

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

728

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0256

AC:

858

AN:

33480

American (AMR)

AF:

0.00136

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00880

AC:

230

AN:

26136

East Asian (EAS)

AF:

0.000302

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000880

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000116

AC:

129

AN:

1112012

Other (OTH)

AF:

0.00263

AC:

159

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

104

208

311

415

519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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

AF:

0.00733

AC:

1117

AN:

152370

Hom.:

Cov.:

AF XY:

0.00693

AC XY:

516

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0243

AC:

1010

AN:

41572

American (AMR)

AF:

0.00261

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3472

East Asian (EAS)

AF:

0.00135

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

68042

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

118

178

237

296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00426

Hom.:

Bravo

AF:

0.00850

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

2.0

(source)

DANN

Benign

0.68

PhyloP100

-0.099

Mutation Taster

=100/0

polymorphism

(source)

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over