NM_001031732.4:c.1678A>G

Variant names:

• chr4-68320129-T-C
• NM_001031732.4:c.1678A>G

Variant summary

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

The NM_001031732.4(YTHDC1):​c.1678A>G​(p.Arg560Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: YTHDC1 NM_001031732.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.69

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 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
YTHDC1	NM_001031732.4	c.1678A>G	p.Arg560Gly	missense_variant	Exon 12 of 17	ENST00000344157.9	NP_001026902.1
YTHDC1	NM_001330698.2	c.1678A>G	p.Arg560Gly	missense_variant	Exon 12 of 17		NP_001317627.1
YTHDC1	NM_133370.4	c.1624A>G	p.Arg542Gly	missense_variant	Exon 11 of 16		NP_588611.2
YTHDC1	XM_005265708.4	c.1624A>G	p.Arg542Gly	missense_variant	Exon 11 of 16		XP_005265765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YTHDC1	ENST00000344157.9	c.1678A>G	p.Arg560Gly	missense_variant	Exon 12 of 17	1	NM_001031732.4	ENSP00000339245.4
YTHDC1	ENST00000355665.7	c.1624A>G	p.Arg542Gly	missense_variant	Exon 11 of 16	1		ENSP00000347888.3
YTHDC1	ENST00000579690.5	c.1678A>G	p.Arg560Gly	missense_variant	Exon 12 of 17	5		ENSP00000463982.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1678A>G (p.R560G) alteration is located in exon 12 (coding exon 12) of the YTHDC1 gene. This alteration results from a A to G substitution at nucleotide position 1678, causing the arginine (R) at amino acid position 560 to be replaced by a glycine (G). 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	0.87
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	T;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.50	D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.3	N;N;.
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;D;.
Sift4G	Benign	0.079	T;T;D
Polyphen		0.98	D;D;.
Vest4		0.76
MutPred		0.17		Loss of methylation at K565 (P = 0.1309);.;Loss of methylation at K565 (P = 0.1309);
MVP		0.13
MPC		1.3
ClinPred		0.90	D
GERP RS		6.2
Varity_R		0.63
gMVP		0.67

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: chr4-69185847;