chr4-68337217-C-G

Variant summary

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

The NM_001031732.4(YTHDC1):ā€‹c.693G>Cā€‹(p.Glu231Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000463 in 1,599,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.000050 ( 0 hom. )

Consequence

YTHDC1
NM_001031732.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.947
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 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=0.082066566).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
YTHDC1NM_001031732.4 linkuse as main transcriptc.693G>C p.Glu231Asp missense_variant 4/17 ENST00000344157.9 NP_001026902.1 Q96MU7-1
YTHDC1NM_001330698.2 linkuse as main transcriptc.693G>C p.Glu231Asp missense_variant 4/17 NP_001317627.1 Q96MU7J3QR07
YTHDC1NM_133370.4 linkuse as main transcriptc.693G>C p.Glu231Asp missense_variant 4/16 NP_588611.2 Q96MU7-2
YTHDC1XM_005265708.4 linkuse as main transcriptc.693G>C p.Glu231Asp missense_variant 4/16 XP_005265765.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
YTHDC1ENST00000344157.9 linkuse as main transcriptc.693G>C p.Glu231Asp missense_variant 4/171 NM_001031732.4 ENSP00000339245.4 Q96MU7-1
YTHDC1ENST00000355665.7 linkuse as main transcriptc.693G>C p.Glu231Asp missense_variant 4/161 ENSP00000347888.3 Q96MU7-2
YTHDC1ENST00000579690.5 linkuse as main transcriptc.693G>C p.Glu231Asp missense_variant 4/175 ENSP00000463982.1 J3QR07

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151934
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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
GnomAD3 exomes
AF:
0.0000448
AC:
11
AN:
245794
Hom.:
0
AF XY:
0.0000527
AC XY:
7
AN XY:
132790
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000295
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000331
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000815
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000497
AC:
72
AN:
1447328
Hom.:
0
Cov.:
29
AF XY:
0.0000527
AC XY:
38
AN XY:
720506
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000451
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000591
Gnomad4 OTH exome
AF:
0.0000501
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151934
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74212
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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
Alfa
AF:
0.0000850
Hom.:
0
ExAC
AF:
0.0000412
AC:
5

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 submitterclinical testingAmbry GeneticsOct 21, 2024The c.693G>C (p.E231D) alteration is located in exon 4 (coding exon 4) of the YTHDC1 gene. This alteration results from a G to C substitution at nucleotide position 693, causing the glutamic acid (E) at amino acid position 231 to be replaced by an aspartic acid (D). 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
0.13
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
18
DANN
Benign
0.94
DEOGEN2
Benign
0.012
T;.;.
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.26
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.86
D;D;T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.082
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.69
N;N;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.020
N;N;.
REVEL
Benign
0.057
Sift
Benign
0.27
T;T;.
Sift4G
Benign
0.51
T;T;T
Polyphen
0.38
B;P;.
Vest4
0.26
MutPred
0.17
Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP
0.17
MPC
0.24
ClinPred
0.058
T
GERP RS
3.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.032
gMVP
0.0025

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.

Other links and lift over

dbSNP: rs780031117; hg19: chr4-69202935; API