NM_138775.3:c.1785delC

Variant names:

• chr11-107504867-AG-A
• rs1591234203
• NM_138775.3:c.1785delC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_138775.3(ALKBH8):​c.1785delC​(p.Trp596GlyfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALKBH8 NM_138775.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.176
• Publications: 0 publications found

Genes affected

ALKBH8 (HGNC:25189): (alkB homolog 8, tRNA methyltransferase) Enables tRNA (uracil) methyltransferase activity; tRNA binding activity; and zinc ion binding activity. Involved in cellular response to DNA damage stimulus; tRNA methylation; and tRNA wobble uridine modification. Located in cytosol and nuclear body. Implicated in autosomal recessive non-syndromic intellectual disability. [provided by Alliance of Genome Resources, Apr 2022]

ALKBH8 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal recessive 71

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.105 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-107504867-AG-A is Pathogenic according to our data. Variant chr11-107504867-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 636272.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138775.3. 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
	ALKBH8	NM_138775.3	MANE Select	c.1785delC	p.Trp596GlyfsTer19	frameshift	Exon 12 of 12	NP_620130.2	Q96BT7-1
	ALKBH8	NM_001301010.3		c.1785delC	p.Trp596GlyfsTer19	frameshift	Exon 12 of 12	NP_001287939.2	Q96BT7-1
	ALKBH8	NM_001378133.1		c.1635delC	p.Trp546GlyfsTer19	frameshift	Exon 11 of 11	NP_001365062.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALKBH8	ENST00000428149.7	TSL:1 MANE Select	c.1785delC	p.Trp596GlyfsTer19	frameshift	Exon 12 of 12	ENSP00000415885.2	Q96BT7-1
	ALKBH8	ENST00000260318.6	TSL:1	n.*590delC		non_coding_transcript_exon	Exon 9 of 9	ENSP00000260318.2	Q96BT7-2
	ALKBH8	ENST00000260318.6	TSL:1	n.*590delC		3_prime_UTR	Exon 9 of 9	ENSP00000260318.2	Q96BT7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual developmental disorder, autosomal recessive 71 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.18
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs1591234203; hg19: chr11-107375593;