chr17-18184674-A-G

Variant names:

• chr17-18184674-A-G
• NM_017758.4:c.431A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017758.4(ALKBH5):​c.431A>G​(p.Gln144Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALKBH5 NM_017758.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.21
• Publications: 0 publications found

Genes affected

ALKBH5 (HGNC:25996): (alkB homolog 5, RNA demethylase) Enables mRNA N6-methyladenosine dioxygenase activity. Involved in RNA metabolic process; mRNA export from nucleus; and response to hypoxia. Located in Golgi apparatus; cytosol; and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000266677 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29217112).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017758.4. 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
	ALKBH5	NM_017758.4	MANE Select	c.431A>G	p.Gln144Arg	missense	Exon 1 of 4	NP_060228.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALKBH5	ENST00000399138.5	TSL:2 MANE Select	c.431A>G	p.Gln144Arg	missense	Exon 1 of 4	ENSP00000382091.4	Q6P6C2-2
	ALKBH5	ENST00000541285.1	TSL:1	c.-254+1409A>G		intron	N/A	ENSP00000468116.1	K7ER58
	ENSG00000266677	ENST00000583062.2	TSL:1	n.118T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460378 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726426

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111518

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.20
Sift	Benign	0.11	T
Sift4G	Uncertain	0.031	D
Vest4		0.38
MutPred		0.40		Gain of MoRF binding (P = 0.0134)
MVP		0.47
MPC		2.8
ClinPred		0.91	D
GERP RS		4.7
Varity_R		0.60
gMVP		0.95
Mutation Taster		=39/61	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

hg19: chr17-18087988;