Variant chr4-68332188-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001031732.4(YTHDC1):c.1037G>A(p.Ser346Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)

Consequence

YTHDC1
NM_001031732.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.48

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:

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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=0.107031584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YTHDC1	NM_001031732.4 linkuse as main transcript	c.1037G>A	p.Ser346Asn	missense_variant	7/17	ENST00000344157.9	NP_001026902.1	Q96MU7-1
YTHDC1	NM_001330698.2 linkuse as main transcript	c.1037G>A	p.Ser346Asn	missense_variant	7/17		NP_001317627.1	Q96MU7J3QR07
YTHDC1	NM_133370.4 linkuse as main transcript	c.983G>A	p.Ser328Asn	missense_variant	6/16		NP_588611.2	Q96MU7-2
YTHDC1	XM_005265708.4 linkuse as main transcript	c.983G>A	p.Ser328Asn	missense_variant	6/16		XP_005265765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
YTHDC1	ENST00000344157.9 linkuse as main transcript	c.1037G>A	p.Ser346Asn	missense_variant	7/17	1	NM_001031732.4	ENSP00000339245.4	Q96MU7-1
YTHDC1	ENST00000355665.7 linkuse as main transcript	c.983G>A	p.Ser328Asn	missense_variant	6/16	1		ENSP00000347888.3	Q96MU7-2
YTHDC1	ENST00000579690.5 linkuse as main transcript	c.1037G>A	p.Ser346Asn	missense_variant	7/17	5		ENSP00000463982.1	J3QR07

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151848

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151848

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74164

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

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 19, 2024

The c.1037G>A (p.S346N) alteration is located in exon 7 (coding exon 7) of the YTHDC1 gene. This alteration results from a G to A substitution at nucleotide position 1037, causing the serine (S) at amino acid position 346 to be replaced by an asparagine (N). 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

0.23

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.018

T;.;.

Eigen

Benign

-0.15

Eigen_PC

Benign

0.090

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;.;.

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.0

N;N;.

REVEL

Benign

0.062

Sift

Benign

0.27

T;T;.

Sift4G

Benign

0.24

T;T;T

Polyphen

0.0030

B;B;.

Vest4

0.21

MutPred

0.24

Loss of phosphorylation at S346 (P = 0.0577);.;Loss of phosphorylation at S346 (P = 0.0577);

MVP

0.043

MPC

0.25

ClinPred

0.70

GERP RS

5.4

Varity_R

0.73

gMVP

0.39

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