chr4-68337208-TTCC-T

Variant names:

• chr4-68337208-TTCC-T
• rs566379464
• NM_001031732.4:c.699_701delGGA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_001031732.4(YTHDC1):​c.699_701delGGA​(p.Glu234del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,589,110 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (9 hom.)
• Consequence: YTHDC1 NM_001031732.4 disruptive_inframe_deletion
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.16
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001031732.4
• BP6: Variant 4-68337208-TTCC-T is Benign according to our data. Variant chr4-68337208-TTCC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3053679.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 398 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031732.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YTHDC1	NM_001031732.4	MANE Select	c.699_701delGGA	p.Glu234del	disruptive_inframe_deletion	Exon 4 of 17	NP_001026902.1	Q96MU7-1
	YTHDC1	NM_001330698.2		c.699_701delGGA	p.Glu234del	disruptive_inframe_deletion	Exon 4 of 17	NP_001317627.1	J3QR07
	YTHDC1	NM_133370.4		c.699_701delGGA	p.Glu234del	disruptive_inframe_deletion	Exon 4 of 16	NP_588611.2	Q96MU7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YTHDC1	ENST00000344157.9	TSL:1 MANE Select	c.699_701delGGA	p.Glu234del	disruptive_inframe_deletion	Exon 4 of 17	ENSP00000339245.4	Q96MU7-1
	YTHDC1	ENST00000355665.7	TSL:1	c.699_701delGGA	p.Glu234del	disruptive_inframe_deletion	Exon 4 of 16	ENSP00000347888.3	Q96MU7-2
	YTHDC1	ENST00000936188.1		c.699_701delGGA	p.Glu234del	disruptive_inframe_deletion	Exon 4 of 18	ENSP00000606247.1

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 151762 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00263

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00890

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00358

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.00248 AC: 608 AN: 244920 AF XY: 0.00243

Gnomad AFR exome AF: 0.000379

Gnomad AMR exome AF: 0.00103

Gnomad ASJ exome AF: 0.000503

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00461

Gnomad NFE exome AF: 0.00399

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00292 AC: 4195 AN: 1437226 Hom.: 9 AF XY: 0.00289 AC XY: 2070 AN XY: 716052

African (AFR) AF: 0.000425 AC: 14 AN: 32952

American (AMR) AF: 0.00115 AC: 51 AN: 44358

Ashkenazi Jewish (ASJ) AF: 0.000501 AC: 13 AN: 25928

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39468

South Asian (SAS) AF: 0.000351 AC: 30 AN: 85424

European-Finnish (FIN) AF: 0.00547 AC: 291 AN: 53156

Middle Eastern (MID) AF: 0.000523 AC: 3 AN: 5740

European-Non Finnish (NFE) AF: 0.00337 AC: 3677 AN: 1090654

Other (OTH) AF: 0.00193 AC: 115 AN: 59546

GnomAD4 genome AF: 0.00262 AC: 398 AN: 151884 Hom.: 2 Cov.: 32 AF XY: 0.00273 AC XY: 203 AN XY: 74228

African (AFR) AF: 0.000362 AC: 15 AN: 41456

American (AMR) AF: 0.00263 AC: 40 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3464

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4780

European-Finnish (FIN) AF: 0.00890 AC: 94 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00358 AC: 243 AN: 67918

Other (OTH) AF: 0.000476 AC: 1 AN: 2102

Alfa AF: 0.000921 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	YTHDC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs566379464; hg19: chr4-69202926;