chr4-68314262-C-T

Position:

chr4-68314262-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001031732.4(YTHDC1):c.2021G>A(p.Arg674Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 0.0000055 ( 0 hom. )

Consequence

YTHDC1
NM_001031732.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.10

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 1 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=0.17976469).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YTHDC1	NM_001031732.4 linkuse as main transcript	c.2021G>A	p.Arg674Gln	missense_variant	17/17	ENST00000344157.9	NP_001026902.1	Q96MU7-1
YTHDC1	NM_001330698.2 linkuse as main transcript	c.2045G>A	p.Arg682Gln	missense_variant	17/17		NP_001317627.1	Q96MU7J3QR07
YTHDC1	NM_133370.4 linkuse as main transcript	c.1967G>A	p.Arg656Gln	missense_variant	16/16		NP_588611.2	Q96MU7-2
YTHDC1	XM_005265708.4 linkuse as main transcript	c.1991G>A	p.Arg664Gln	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.2021G>A	p.Arg674Gln	missense_variant	17/17	1	NM_001031732.4	ENSP00000339245.4	Q96MU7-1
YTHDC1	ENST00000355665.7 linkuse as main transcript	c.1967G>A	p.Arg656Gln	missense_variant	16/16	1		ENSP00000347888.3	Q96MU7-2
YTHDC1	ENST00000579690.5 linkuse as main transcript	c.2045G>A	p.Arg682Gln	missense_variant	17/17	5		ENSP00000463982.1	J3QR07

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.00000399

AC:

AN:

250554

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135410

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727222

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

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:

0.0000370

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

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

Mar 01, 2023

The c.2021G>A (p.R674Q) alteration is located in exon 17 (coding exon 17) of the YTHDC1 gene. This alteration results from a G to A substitution at nucleotide position 2021, causing the arginine (R) at amino acid position 674 to be replaced by a glutamine (Q). 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

0.65

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Benign

0.92

DEOGEN2

Benign

0.020

T;.;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.2

N;N;.

REVEL

Benign

0.15

Sift

Benign

0.69

T;T;.

Sift4G

Benign

0.21

T;T;T

Polyphen

0.96

D;D;.

Vest4

0.42

MVP

0.068

MPC

0.69

ClinPred

0.76

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.16

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