19-36009486-C-T

Variant names:

• chr19-36009486-C-T
• rs1399385659
• NM_032878.5:c.521G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032878.5(ALKBH6):​c.521G>A​(p.Gly174Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,080 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G174R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALKBH6 NM_032878.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58
• Publications: 0 publications found

Genes affected

ALKBH6 (HGNC:28243): (alkB homolog 6) Predicted to enable dioxygenase activity and metal ion binding activity. Located in focal adhesion and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000248101 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.095568806).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032878.5. 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
	ALKBH6	NM_032878.5	MANE Select	c.521G>A	p.Gly174Asp	missense	Exon 7 of 7	NP_116267.4
	ALKBH6	NM_001297701.2		c.521G>A	p.Gly174Asp	missense	Exon 8 of 8	NP_001284630.1	Q3KRA9-1
	ALKBH6	NM_001386055.1		c.521G>A	p.Gly174Asp	missense	Exon 7 of 7	NP_001372984.1	Q3KRA9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALKBH6	ENST00000378875.8	TSL:1 MANE Select	c.521G>A	p.Gly174Asp	missense	Exon 7 of 7	ENSP00000368152.4	Q3KRA9-1
	ALKBH6	ENST00000252984.11	TSL:1	c.521G>A	p.Gly174Asp	missense	Exon 8 of 8	ENSP00000252984.6	Q3KRA9-1
	ALKBH6	ENST00000490986.5	TSL:1	n.*214G>A		non_coding_transcript_exon	Exon 7 of 7	ENSP00000435496.1	H0YEC4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1097058 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 519662

African (AFR) AF: 0.00 AC: 0 AN: 23440

American (AMR) AF: 0.00 AC: 0 AN: 9548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14566

East Asian (EAS) AF: 0.00 AC: 0 AN: 27198

South Asian (SAS) AF: 0.00 AC: 0 AN: 21598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 930656

Other (OTH) AF: 0.00 AC: 0 AN: 44450

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74294

African (AFR) AF: 0.0000241 AC: 1 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

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	Uncertain	0.35
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.069
Eigen_PC	Benign	0.043
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.090	N
PhyloP100		1.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	1.3	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0060	B
Vest4		0.33
MutPred		0.57		Loss of methylation at R173 (P = 0.036)
MVP		0.20
MPC		2.2
ClinPred		0.20	T
GERP RS		5.4
Varity_R		0.26
gMVP		0.64
Mutation Taster		=91/9	polymorphism

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

dbSNP: rs1399385659; hg19: chr19-36500388; COSMIC: COSV53323885; COSMIC: COSV53323885;