4-68318532-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001031732.4(YTHDC1):​c.1811C>T​(p.Pro604Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000844 in 1,611,606 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

YTHDC1
NM_001031732.4 missense

Scores

4
10
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.81
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
YTHDC1NM_001031732.4 linkc.1811C>T p.Pro604Leu missense_variant Exon 15 of 17 ENST00000344157.9 NP_001026902.1 Q96MU7-1
YTHDC1NM_001330698.2 linkc.1835C>T p.Pro612Leu missense_variant Exon 15 of 17 NP_001317627.1 Q96MU7J3QR07
YTHDC1NM_133370.4 linkc.1757C>T p.Pro586Leu missense_variant Exon 14 of 16 NP_588611.2 Q96MU7-2
YTHDC1XM_005265708.4 linkc.1781C>T p.Pro594Leu missense_variant Exon 14 of 16 XP_005265765.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
YTHDC1ENST00000344157.9 linkc.1811C>T p.Pro604Leu missense_variant Exon 15 of 17 1 NM_001031732.4 ENSP00000339245.4 Q96MU7-1
YTHDC1ENST00000355665.7 linkc.1757C>T p.Pro586Leu missense_variant Exon 14 of 16 1 ENSP00000347888.3 Q96MU7-2
YTHDC1ENST00000579690.5 linkc.1835C>T p.Pro612Leu missense_variant Exon 15 of 17 5 ENSP00000463982.1 J3QR07
YTHDC1ENST00000507529.1 linkc.80C>T p.Pro27Leu missense_variant Exon 2 of 3 3 ENSP00000461990.1 J3KRG5

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152178
Hom.:
0
Cov.:
32
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000521
AC:
13
AN:
249648
Hom.:
0
AF XY:
0.0000444
AC XY:
6
AN XY:
135188
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000583
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:
0.0000972
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000911
AC:
133
AN:
1459428
Hom.:
0
Cov.:
31
AF XY:
0.0000868
AC XY:
63
AN XY:
726004
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000450
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:
0.000112
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74334
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:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.0000577
AC:
7
EpiCase
AF:
0.000327
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
May 10, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1811C>T (p.P604L) alteration is located in exon 15 (coding exon 15) of the YTHDC1 gene. This alteration results from a C to T substitution at nucleotide position 1811, causing the proline (P) at amino acid position 604 to be replaced by a leucine (L). 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
Uncertain
0.42
BayesDel_addAF
Uncertain
0.049
T
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.28
T;.;.
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Uncertain
0.59
D;D;D
MetaSVM
Uncertain
-0.095
T
MutationAssessor
Benign
1.8
L;.;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-5.7
D;D;.
REVEL
Uncertain
0.52
Sift
Benign
0.053
T;T;.
Sift4G
Benign
0.092
T;T;T
Polyphen
1.0
D;D;.
Vest4
0.66
MVP
0.34
MPC
1.6
ClinPred
0.61
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.48
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs149734797; hg19: chr4-69184250; API