4-68314190-T-C

Position:

• chr4-68314190-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001031732.4(YTHDC1):​c.2093A>G​(p.Glu698Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,474 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: YTHDC1 NM_001031732.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.50

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 1 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=0.12210372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YTHDC1	NM_001031732.4	c.2093A>G	p.Glu698Gly	missense_variant	17/17	ENST00000344157.9	NP_001026902.1
YTHDC1	NM_001330698.2	c.2117A>G	p.Glu706Gly	missense_variant	17/17		NP_001317627.1
YTHDC1	NM_133370.4	c.2039A>G	p.Glu680Gly	missense_variant	16/16		NP_588611.2
YTHDC1	XM_005265708.4	c.2063A>G	p.Glu688Gly	missense_variant	16/16		XP_005265765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
YTHDC1	ENST00000344157.9	c.2093A>G	p.Glu698Gly	missense_variant	17/17	1	NM_001031732.4	ENSP00000339245.4
YTHDC1	ENST00000355665.7	c.2039A>G	p.Glu680Gly	missense_variant	16/16	1		ENSP00000347888.3
YTHDC1	ENST00000579690.5	c.2117A>G	p.Glu706Gly	missense_variant	17/17	5		ENSP00000463982.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461474 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727028

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Aug 14, 2024

The c.2093A>G (p.E698G) alteration is located in exon 17 (coding exon 17) of the YTHDC1 gene. This alteration results from a A to G substitution at nucleotide position 2093, causing the glutamic acid (E) at amino acid position 698 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	Uncertain	0.49
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T;.;.
Eigen	Benign	-0.058
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.5	N;N;.
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D;D;.
Sift4G	Benign	0.19	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.19
MutPred		0.20		Loss of helix (P = 0.0237);.;.;
MVP		0.043
MPC		0.70
ClinPred		0.62	D
GERP RS		5.6
Varity_R		0.17
gMVP		0.089

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

LitVar

Other links and lift over

dbSNP: rs1721562357; hg19: chr4-69179908;