NM_138775.3:c.1834G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_138775.3(ALKBH8):c.1834G>T(p.Gly612Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,551,738 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.018 ( 91 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 65 hom. )

Consequence

ALKBH8
NM_138775.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.865

Publications

4 publications found

Variant links:

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

ALKBH8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003430456).

BP6

Variant 11-107504819-C-A is Benign according to our data. Variant chr11-107504819-C-A is described in ClinVar as Benign. ClinVar VariationId is 3043881.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0596 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALKBH8	NM_138775.3	MANE Select	c.1834G>T	p.Gly612Cys	missense	Exon 12 of 12	NP_620130.2	Q96BT7-1
ALKBH8	NM_001301010.3		c.1834G>T	p.Gly612Cys	missense	Exon 12 of 12	NP_001287939.2	Q96BT7-1
ALKBH8	NM_001378133.1		c.1684G>T	p.Gly562Cys	missense	Exon 11 of 11	NP_001365062.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALKBH8	ENST00000428149.7	TSL:1 MANE Select	c.1834G>T	p.Gly612Cys	missense	Exon 12 of 12	ENSP00000415885.2	Q96BT7-1
ALKBH8	ENST00000260318.6	TSL:1	n.*639G>T		non_coding_transcript_exon	Exon 9 of 9	ENSP00000260318.2	Q96BT7-2
ALKBH8	ENST00000260318.6	TSL:1	n.*639G>T		3_prime_UTR	Exon 9 of 9	ENSP00000260318.2	Q96BT7-2

Frequencies

GnomAD3 genomes

AF:

0.0177

AC:

2690

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0615

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00635

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00412

AC:

649

AN:

157446

AF XY:

0.00328

show subpopulations

Gnomad AFR exome

AF:

0.0661

Gnomad AMR exome

AF:

0.00336

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000360

Gnomad OTH exome

AF:

0.00113

GnomAD4 exome

AF:

0.00183

AC:

2556

AN:

1399550

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

1113

AN XY:

690278

show subpopulations

African (AFR)

AF:

0.0619

AC:

1956

AN:

31588

American (AMR)

AF:

0.00347

AC:

124

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25174

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.000202

AC:

AN:

79228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49368

Middle Eastern (MID)

AF:

0.00263

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.000154

AC:

166

AN:

1078988

Other (OTH)

AF:

0.00480

AC:

279

AN:

58068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

149

298

447

596

745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0177

AC:

2697

AN:

152188

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1287

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0616

AC:

2556

AN:

41518

American (AMR)

AF:

0.00635

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68010

Other (OTH)

AF:

0.0104

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

124

248

371

495

619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00692

Hom.:

Bravo

AF:

0.0207

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0658

AC:

ESP6500EA

AF:

0.000629

AC:

ExAC

AF:

0.00713

AC:

180

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

ALKBH8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.059

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0034

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PhyloP100

0.86

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.6

REVEL

Benign

0.066

Sift

Benign

0.090

Sift4G

Uncertain

0.029

Polyphen

0.99

Vest4

0.26

MVP

0.27

MPC

0.041

ClinPred

0.018

GERP RS

3.4

Varity_R

0.076

gMVP

0.35

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over