4-68333378-C-G

Position:

• chr4-68333378-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001031732.4(YTHDC1):​c.903G>C​(p.Arg301Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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: not found (cov: 32)
• Consequence: YTHDC1 NM_001031732.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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]

ACMG classification

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=0.12235615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YTHDC1	NM_001031732.4	c.903G>C	p.Arg301Ser	missense_variant	5/17	ENST00000344157.9	NP_001026902.1
YTHDC1	NM_001330698.2	c.903G>C	p.Arg301Ser	missense_variant	5/17		NP_001317627.1
YTHDC1	NM_133370.4	c.903G>C	p.Arg301Ser	missense_variant	5/16		NP_588611.2
YTHDC1	XM_005265708.4	c.903G>C	p.Arg301Ser	missense_variant	5/16		XP_005265765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
YTHDC1	ENST00000344157.9	c.903G>C	p.Arg301Ser	missense_variant	5/17	1	NM_001031732.4	ENSP00000339245.4
YTHDC1	ENST00000355665.7	c.903G>C	p.Arg301Ser	missense_variant	5/16	1		ENSP00000347888.3
YTHDC1	ENST00000579690.5	c.903G>C	p.Arg301Ser	missense_variant	5/17	5		ENSP00000463982.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2024

The c.903G>C (p.R301S) alteration is located in exon 5 (coding exon 5) of the YTHDC1 gene. This alteration results from a G to C substitution at nucleotide position 903, causing the arginine (R) at amino acid position 301 to be replaced by a serine (S). 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	0.79
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.023	T;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.92	N;N;.
REVEL	Benign	0.15
Sift	Benign	0.030	D;D;.
Sift4G	Uncertain	0.022	D;T;D
Polyphen		0.25	B;D;.
Vest4		0.24
MutPred		0.27		Gain of phosphorylation at R301 (P = 0.0056);Gain of phosphorylation at R301 (P = 0.0056);Gain of phosphorylation at R301 (P = 0.0056);
MVP		0.068
MPC		0.34
ClinPred		0.79	D
GERP RS		-0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.46
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-69199096;