4-68320204-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001031732.4(YTHDC1):​c.1603C>T​(p.Arg535Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,600,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

YTHDC1
NM_001031732.4 missense, splice_region

Scores

2
4
13
Splicing: ADA: 0.9837
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.48
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
YTHDC1NM_001031732.4 linkc.1603C>T p.Arg535Cys missense_variant, splice_region_variant Exon 12 of 17 ENST00000344157.9 NP_001026902.1 Q96MU7-1
YTHDC1NM_001330698.2 linkc.1603C>T p.Arg535Cys missense_variant, splice_region_variant Exon 12 of 17 NP_001317627.1 Q96MU7J3QR07
YTHDC1NM_133370.4 linkc.1549C>T p.Arg517Cys missense_variant, splice_region_variant Exon 11 of 16 NP_588611.2 Q96MU7-2
YTHDC1XM_005265708.4 linkc.1549C>T p.Arg517Cys missense_variant, splice_region_variant Exon 11 of 16 XP_005265765.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
YTHDC1ENST00000344157.9 linkc.1603C>T p.Arg535Cys missense_variant, splice_region_variant Exon 12 of 17 1 NM_001031732.4 ENSP00000339245.4 Q96MU7-1
YTHDC1ENST00000355665.7 linkc.1549C>T p.Arg517Cys missense_variant, splice_region_variant Exon 11 of 16 1 ENSP00000347888.3 Q96MU7-2
YTHDC1ENST00000579690.5 linkc.1603C>T p.Arg535Cys missense_variant, splice_region_variant Exon 12 of 17 5 ENSP00000463982.1 J3QR07

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
151932
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000289
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000168
AC:
4
AN:
238506
Hom.:
0
AF XY:
0.0000155
AC XY:
2
AN XY:
129144
show subpopulations
Gnomad AFR exome
AF:
0.0000632
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000103
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000181
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000759
AC:
11
AN:
1448604
Hom.:
0
Cov.:
30
AF XY:
0.00000694
AC XY:
5
AN XY:
720526
show subpopulations
Gnomad4 AFR exome
AF:
0.0000306
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000902
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
151932
Hom.:
0
Cov.:
32
AF XY:
0.0000270
AC XY:
2
AN XY:
74200
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000289
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 07, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1603C>T (p.R535C) alteration is located in exon 12 (coding exon 12) of the YTHDC1 gene. This alteration results from a C to T substitution at nucleotide position 1603, causing the arginine (R) at amino acid position 535 to be replaced by a cysteine (C). 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
0.30
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.33
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
T;.;.
Eigen
Benign
0.17
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.21
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.7
L;.;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-3.1
D;D;.
REVEL
Benign
0.13
Sift
Benign
0.042
D;D;.
Sift4G
Benign
0.15
T;T;T
Polyphen
0.069
B;B;.
Vest4
0.52
MutPred
0.25
Loss of MoRF binding (P = 0.0196);.;Loss of MoRF binding (P = 0.0196);
MVP
0.043
MPC
0.85
ClinPred
0.50
D
GERP RS
6.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.34
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.98
dbscSNV1_RF
Pathogenic
0.81
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.

Other links and lift over

dbSNP: rs763027992; hg19: chr4-69185922; COSMIC: COSV100704912; COSMIC: COSV100704912; API