Genetic Variant NM_138775.3:c.1588_1590delGAG (chr11-107505062-TCTC-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PM4_Supporting

The NM_138775.3(ALKBH8):c.1588_1590delGAG(p.Glu530del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,402 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E530E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ALKBH8
NM_138775.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.494

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_138775.3. Strenght limited to Supporting due to length of the change: 1aa.

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.1588_1590delGAG	p.Glu530del	conservative_inframe_deletion	Exon 12 of 12	NP_620130.2	Q96BT7-1
ALKBH8	NM_001301010.3		c.1588_1590delGAG	p.Glu530del	conservative_inframe_deletion	Exon 12 of 12	NP_001287939.2	Q96BT7-1
ALKBH8	NM_001378133.1		c.1438_1440delGAG	p.Glu480del	conservative_inframe_deletion	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.1588_1590delGAG	p.Glu530del	conservative_inframe_deletion	Exon 12 of 12	ENSP00000415885.2	Q96BT7-1
ALKBH8	ENST00000260318.6	TSL:1	n.393_395delGAG		non_coding_transcript_exon	Exon 9 of 9	ENSP00000260318.2	Q96BT7-2
ALKBH8	ENST00000260318.6	TSL:1	n.393_395delGAG		3_prime_UTR	Exon 9 of 9	ENSP00000260318.2	Q96BT7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1399402

Hom.:

AF XY:

0.00000145

AC XY:

AN XY:

690194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31590

American (AMR)

AF:

0.00

AC:

AN:

35706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.00

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49276

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1078952

Other (OTH)

AF:

0.00

AC:

AN:

58026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual developmental disorder, autosomal recessive 71 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.49

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over