4-68314109-T-A

Position:

chr4-68314109-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001031732.4(YTHDC1):c.2174A>T(p.Tyr725Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000545 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

YTHDC1
NM_001031732.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.69

Variant links:

Genes affected

YTHDC1 (HGNC:30626): (YTH N6-methyladenosine RNA binding protein C1) Enables N6-methyladenosine-containing RNA binding activity. Involved in mRNA export from nucleus; mRNA splice site selection; and regulation of gene expression. Located in nuclear speck and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

YTHDC1 links:

Genome browser will be placed here

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;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), YTHDC1. . Gene score misZ 2.4773 (greater than the threshold 3.09). Trascript score misZ 3.4335 (greater than threshold 3.09). GenCC has associacion of gene with autism spectrum disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.36217737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YTHDC1	NM_001031732.4 linkuse as main transcript	c.2174A>T	p.Tyr725Phe	missense_variant	17/17	ENST00000344157.9	NP_001026902.1	Q96MU7-1
YTHDC1	NM_001330698.2 linkuse as main transcript	c.2198A>T	p.Tyr733Phe	missense_variant	17/17		NP_001317627.1	Q96MU7J3QR07
YTHDC1	NM_133370.4 linkuse as main transcript	c.2120A>T	p.Tyr707Phe	missense_variant	16/16		NP_588611.2	Q96MU7-2
YTHDC1	XM_005265708.4 linkuse as main transcript	c.2144A>T	p.Tyr715Phe	missense_variant	16/16		XP_005265765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
YTHDC1	ENST00000344157.9 linkuse as main transcript	c.2174A>T	p.Tyr725Phe	missense_variant	17/17	1	NM_001031732.4	ENSP00000339245.4	Q96MU7-1
YTHDC1	ENST00000355665.7 linkuse as main transcript	c.2120A>T	p.Tyr707Phe	missense_variant	16/16	1		ENSP00000347888.3	Q96MU7-2
YTHDC1	ENST00000579690.5 linkuse as main transcript	c.2198A>T	p.Tyr733Phe	missense_variant	17/17	5		ENSP00000463982.1	J3QR07

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251164

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135760

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000728

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.2174A>T (p.Y725F) alteration is located in exon 17 (coding exon 17) of the YTHDC1 gene. This alteration results from a A to T substitution at nucleotide position 2174, causing the tyrosine (Y) at amino acid position 725 to be replaced by a phenylalanine (F). 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

Benign

0.31

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.031

T;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.36

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.69

N;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.3

N;N;.

REVEL

Benign

0.22

Sift

Pathogenic

0.0

D;D;.

Sift4G

Benign

0.15

T;T;T

Polyphen

0.96

P;D;.

Vest4

0.58

MVP

0.16

MPC

0.55

ClinPred

0.41

GERP RS

5.7

Varity_R

0.25

gMVP

0.027

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