4-68314262-C-A

Variant names:

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

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>T​(p.Arg674Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: YTHDC1 NM_001031732.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.10
• Publications: 0 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=0.3863826).

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>T	p.Arg674Leu	missense	Exon 17 of 17	NP_001026902.1	Q96MU7-1
	YTHDC1	NM_001330698.2		c.2045G>T	p.Arg682Leu	missense	Exon 17 of 17	NP_001317627.1	J3QR07
	YTHDC1	NM_133370.4		c.1967G>T	p.Arg656Leu	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>T	p.Arg674Leu	missense	Exon 17 of 17	ENSP00000339245.4	Q96MU7-1
	YTHDC1	ENST00000355665.7	TSL:1	c.1967G>T	p.Arg656Leu	missense	Exon 16 of 16	ENSP00000347888.3	Q96MU7-2
	YTHDC1	ENST00000936188.1		c.2114G>T	p.Arg705Leu	missense	Exon 18 of 18	ENSP00000606247.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	0.0073	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.035
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.20
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.10	T
Polyphen		0.0020	B
Vest4		0.68
MutPred		0.25		Loss of sheet (P = 0.0104)
MVP		0.068
MPC		0.74
ClinPred		0.91	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.23
Mutation Taster		=58/42	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

Other links and lift over

dbSNP: rs751003108; hg19: chr4-69179980;