4-68320129-T-C

Position:

• chr4-68320129-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YTHDC1	NM_001031732.4	c.1678A>G	p.Arg560Gly	missense_variant	12/17	ENST00000344157.9	NP_001026902.1
YTHDC1	NM_001330698.2	c.1678A>G	p.Arg560Gly	missense_variant	12/17		NP_001317627.1
YTHDC1	NM_133370.4	c.1624A>G	p.Arg542Gly	missense_variant	11/16		NP_588611.2
YTHDC1	XM_005265708.4	c.1624A>G	p.Arg542Gly	missense_variant	11/16		XP_005265765.1

Ensembl

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

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;