chr17-18184290-C-A

Position:

• chr17-18184290-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017758.4(ALKBH5):​c.47C>A​(p.Ser16Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALKBH5 NM_017758.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.97

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALKBH5	NM_017758.4	c.47C>A	p.Ser16Tyr	missense_variant	1/4	ENST00000399138.5	NP_060228.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALKBH5	ENST00000399138.5	c.47C>A	p.Ser16Tyr	missense_variant	1/4	2	NM_017758.4	ENSP00000382091.4
ALKBH5	ENST00000541285.1	c.-254+1025C>A		intron_variant		1		ENSP00000468116.1
ENSG00000266677	ENST00000583062.1	n.357+107G>T		intron_variant		1
ENSG00000266677	ENST00000577847.1	n.271+107G>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1375594 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 678970

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2024

The c.47C>A (p.S16Y) alteration is located in exon 1 (coding exon 1) of the ALKBH5 gene. This alteration results from a C to A substitution at nucleotide position 47, causing the serine (S) at amino acid position 16 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.054	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.5	L
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Vest4		0.52
MutPred		0.22		Loss of methylation at K13 (P = 0.082);
MVP		0.30
MPC		3.2
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.79
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs2047121417; hg19: chr17-18087604;