NM_138775.3:c.1966A>C

Variant names:

• chr11-107504687-T-G
• rs1565307598
• NM_138775.3:c.1966A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_138775.3(ALKBH8):​c.1966A>C​(p.Asn656His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000716 in 1,397,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N656K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: ALKBH8 NM_138775.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74
• 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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

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.1966A>C	p.Asn656His	missense	Exon 12 of 12	NP_620130.2	Q96BT7-1
	ALKBH8	NM_001301010.3		c.1966A>C	p.Asn656His	missense	Exon 12 of 12	NP_001287939.2	Q96BT7-1
	ALKBH8	NM_001378133.1		c.1816A>C	p.Asn606His	missense	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.1966A>C	p.Asn656His	missense	Exon 12 of 12	ENSP00000415885.2	Q96BT7-1
	ALKBH8	ENST00000260318.6	TSL:1	n.*771A>C		non_coding_transcript_exon	Exon 9 of 9	ENSP00000260318.2	Q96BT7-2
	ALKBH8	ENST00000260318.6	TSL:1	n.*771A>C		3_prime_UTR	Exon 9 of 9	ENSP00000260318.2	Q96BT7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000641 AC: 1 AN: 155902 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000164

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000716 AC: 10 AN: 1397056 Hom.: 0 Cov.: 31 AF XY: 0.00000726 AC XY: 5 AN XY: 689002

African (AFR) AF: 0.0000318 AC: 1 AN: 31408

American (AMR) AF: 0.00 AC: 0 AN: 35156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24942

East Asian (EAS) AF: 0.00 AC: 0 AN: 35724

South Asian (SAS) AF: 0.00 AC: 0 AN: 78906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.00000835 AC: 9 AN: 1077828

Other (OTH) AF: 0.00 AC: 0 AN: 58016

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000488 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		7.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.84		Gain of disorder (P = 0.0879)
MVP		0.84
MPC		0.064
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.78
gMVP		0.72
Mutation Taster		=29/71	disease causing

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: rs1565307598; hg19: chr11-107375413;