chr4-68332838-T-C

Variant names:

• chr4-68332838-T-C
• rs1723744353
• NM_001031732.4:c.983A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001031732.4(YTHDC1):​c.983A>G​(p.Lys328Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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: 5.35

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13456526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YTHDC1	NM_001031732.4	c.983A>G	p.Lys328Arg	missense_variant	Exon 6 of 17	ENST00000344157.9	NP_001026902.1
YTHDC1	NM_001330698.2	c.983A>G	p.Lys328Arg	missense_variant	Exon 6 of 17		NP_001317627.1
YTHDC1	NM_133370.4	c.973+470A>G		intron_variant	Intron 5 of 15		NP_588611.2
YTHDC1	XM_005265708.4	c.973+470A>G		intron_variant	Intron 5 of 15		XP_005265765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YTHDC1	ENST00000344157.9	c.983A>G	p.Lys328Arg	missense_variant	Exon 6 of 17	1	NM_001031732.4	ENSP00000339245.4
YTHDC1	ENST00000355665.7	c.973+470A>G		intron_variant	Intron 5 of 15	1		ENSP00000347888.3
YTHDC1	ENST00000579690.5	c.983A>G	p.Lys328Arg	missense_variant	Exon 6 of 17	5		ENSP00000463982.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.983A>G (p.K328R) alteration is located in exon 6 (coding exon 6) of the YTHDC1 gene. This alteration results from a A to G substitution at nucleotide position 983, causing the lysine (K) at amino acid position 328 to be replaced by an arginine (R). 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	Benign	0.15
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Benign	0.020	T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.096
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.087
Sift	Benign	0.17	T;.
Sift4G	Benign	0.25	T;T
Polyphen		0.024	B;.
Vest4		0.45
MutPred		0.15		Loss of ubiquitination at K328 (P = 0.0063);Loss of ubiquitination at K328 (P = 0.0063);
MVP		0.12
MPC		0.33
ClinPred		0.71	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.38

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: rs1723744353; hg19: chr4-69198556;