chr11-107504978-G-A

Variant names:

• chr11-107504978-G-A
• rs577135985
• NM_138775.3:c.1675C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138775.3(ALKBH8):​c.1675C>T​(p.Arg559Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000643 in 1,399,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. R559H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: ALKBH8 NM_138775.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.246
• Publications: 1 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048407137).

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.1675C>T	p.Arg559Cys	missense	Exon 12 of 12	NP_620130.2	Q96BT7-1
	ALKBH8	NM_001301010.3		c.1675C>T	p.Arg559Cys	missense	Exon 12 of 12	NP_001287939.2	Q96BT7-1
	ALKBH8	NM_001378133.1		c.1525C>T	p.Arg509Cys	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.1675C>T	p.Arg559Cys	missense	Exon 12 of 12	ENSP00000415885.2	Q96BT7-1
	ALKBH8	ENST00000260318.6	TSL:1	n.*480C>T		non_coding_transcript_exon	Exon 9 of 9	ENSP00000260318.2	Q96BT7-2
	ALKBH8	ENST00000260318.6	TSL:1	n.*480C>T		3_prime_UTR	Exon 9 of 9	ENSP00000260318.2	Q96BT7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000190 AC: 3 AN: 157580 AF XY: 0.0000120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000917

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000163

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000643 AC: 9 AN: 1399338 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 690120

African (AFR) AF: 0.0000317 AC: 1 AN: 31584

American (AMR) AF: 0.0000280 AC: 1 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49392

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5698

European-Non Finnish (NFE) AF: 0.00000463 AC: 5 AN: 1078788

Other (OTH) AF: 0.00 AC: 0 AN: 58104

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000165 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000392 AC: 1

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	Benign	0.068
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.8
DANN	Benign	0.91
DEOGEN2	Benign	0.032	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N
PhyloP100		-0.25
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.016
Sift	Benign	0.065	T
Sift4G	Uncertain	0.055	T
Polyphen		0.0	B
Vest4		0.079
MutPred		0.44		Gain of catalytic residue at P558 (P = 0.0103)
MVP		0.055
MPC		0.0096
ClinPred		0.030	T
GERP RS		-2.0
Varity_R		0.039
gMVP		0.29
Mutation Taster		=94/6	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: rs577135985; hg19: chr11-107375704; COSMIC: COSV106374944;