chr4-68322785-C-T

Position:

• chr4-68322785-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001031732.4(YTHDC1):​c.1565G>A​(p.Arg522His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: YTHDC1 NM_001031732.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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=0.32415098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YTHDC1	NM_001031732.4	c.1565G>A	p.Arg522His	missense_variant	11/17	ENST00000344157.9	NP_001026902.1
YTHDC1	NM_001330698.2	c.1565G>A	p.Arg522His	missense_variant	11/17		NP_001317627.1
YTHDC1	NM_133370.4	c.1511G>A	p.Arg504His	missense_variant	10/16		NP_588611.2
YTHDC1	XM_005265708.4	c.1511G>A	p.Arg504His	missense_variant	10/16		XP_005265765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
YTHDC1	ENST00000344157.9	c.1565G>A	p.Arg522His	missense_variant	11/17	1	NM_001031732.4	ENSP00000339245.4
YTHDC1	ENST00000355665.7	c.1511G>A	p.Arg504His	missense_variant	10/16	1		ENSP00000347888.3
YTHDC1	ENST00000579690.5	c.1565G>A	p.Arg522His	missense_variant	11/17	5		ENSP00000463982.1
YTHDC1	ENST00000506175.1	n.288G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461832 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

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

Jan 24, 2024

The c.1565G>A (p.R522H) alteration is located in exon 11 (coding exon 11) of the YTHDC1 gene. This alteration results from a G to A substitution at nucleotide position 1565, causing the arginine (R) at amino acid position 522 to be replaced by a histidine (H). 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T;.;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	0.010	N;N;.
REVEL	Benign	0.25
Sift	Uncertain	0.0070	D;D;.
Sift4G	Benign	0.26	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.55
MutPred		0.24		Loss of methylation at R522 (P = 0.0244);.;Loss of methylation at R522 (P = 0.0244);
MVP		0.068
MPC		1.7
ClinPred		0.78	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1328195861; hg19: chr4-69188503;