11-43901545-C-A

Variant names:

• chr11-43901545-C-A
• rs764403690
• NM_139178.4:c.489C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_139178.4(ALKBH3):​c.489C>A​(p.Asn163Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALKBH3 NM_139178.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.949

Genes affected

ALKBH3 (HGNC:30141): (alkB homolog 3, alpha-ketoglutarate dependent dioxygenase) The Escherichia coli AlkB protein protects against the cytotoxicity of methylating agents by repair of the specific DNA lesions generated in single-stranded DNA. ALKBH2 (MIM 610602) and ALKBH3 are E. coli AlkB homologs that catalyze the removal of 1-methyladenine and 3-methylcytosine (Duncan et al., 2002 [PubMed 12486230]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06703922).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALKBH3	NM_139178.4	c.489C>A	p.Asn163Lys	missense_variant	Exon 8 of 10	ENST00000302708.9	NP_631917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALKBH3	ENST00000302708.9	c.489C>A	p.Asn163Lys	missense_variant	Exon 8 of 10	1	NM_139178.4	ENSP00000302232.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.489C>A (p.N163K) alteration is located in exon 8 (coding exon 7) of the ALKBH3 gene. This alteration results from a C to A substitution at nucleotide position 489, causing the asparagine (N) at amino acid position 163 to be replaced by a lysine (K). 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	Benign	0.091
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Benign	0.80
DEOGEN2	Benign	0.026	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.43	T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.19	N;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.52	N;N
REVEL	Benign	0.069
Sift	Benign	0.74	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.0	B;.
Vest4		0.14
MutPred		0.33		Gain of methylation at N163 (P = 0.038);.;
MVP		0.23
MPC		0.064
ClinPred		0.049	T
GERP RS		0.084
Varity_R		0.13
gMVP		0.23

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: rs764403690; hg19: chr11-43923095;