4-68314262-C-G

Variant names:

• chr4-68314262-C-G
• rs751003108
• NM_001031732.4:c.2021G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001031732.4(YTHDC1):​c.2021G>C​(p.Arg674Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R674Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: YTHDC1 NM_001031732.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.10
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2760054).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031732.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YTHDC1	NM_001031732.4	MANE Select	c.2021G>C	p.Arg674Pro	missense	Exon 17 of 17	NP_001026902.1	Q96MU7-1
	YTHDC1	NM_001330698.2		c.2045G>C	p.Arg682Pro	missense	Exon 17 of 17	NP_001317627.1	J3QR07
	YTHDC1	NM_133370.4		c.1967G>C	p.Arg656Pro	missense	Exon 16 of 16	NP_588611.2	Q96MU7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YTHDC1	ENST00000344157.9	TSL:1 MANE Select	c.2021G>C	p.Arg674Pro	missense	Exon 17 of 17	ENSP00000339245.4	Q96MU7-1
	YTHDC1	ENST00000355665.7	TSL:1	c.1967G>C	p.Arg656Pro	missense	Exon 16 of 16	ENSP00000347888.3	Q96MU7-2
	YTHDC1	ENST00000936188.1		c.2114G>C	p.Arg705Pro	missense	Exon 18 of 18	ENSP00000606247.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
PhyloP100		7.1
Varity_R		0.59
gMVP		0.25
Mutation Taster		=52/48	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs751003108; hg19: chr4-69179980;