7-102457521-A-G

Position:

• chr7-102457521-A-G

Variant summary

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

The ENST00000292566.4(ALKBH4):​c.782T>C​(p.Ile261Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ALKBH4 ENST00000292566.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.65

Genes affected

ALKBH4 (HGNC:21900): (alkB homolog 4, lysine demethylase) Enables 2-oxoglutarate-dependent dioxygenase activity and actin binding activity. Involved in actomyosin structure organization; cleavage furrow ingression; and protein demethylation. Located in contractile ring and midbody. [provided by Alliance of Genome Resources, Apr 2022]

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
ALKBH4	NM_017621.4	c.782T>C	p.Ile261Thr	missense_variant	3/3	ENST00000292566.4	NP_060091.1
ALKBH4	XM_005250464.4	c.563T>C	p.Ile188Thr	missense_variant	3/3		XP_005250521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALKBH4	ENST00000292566.4	c.782T>C	p.Ile261Thr	missense_variant	3/3	1	NM_017621.4	ENSP00000292566.3
ALKBH4	ENST00000490528.1	n.*562T>C		non_coding_transcript_exon_variant	3/3	2		ENSP00000420362.1
ALKBH4	ENST00000490528.1	n.*562T>C		3_prime_UTR_variant	3/3	2		ENSP00000420362.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460568 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726644

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 13, 2022

The c.782T>C (p.I261T) alteration is located in exon 3 (coding exon 3) of the ALKBH4 gene. This alteration results from a T to C substitution at nucleotide position 782, causing the isoleucine (I) at amino acid position 261 to be replaced by a threonine (T). 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	Uncertain	0.44
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.56
MutPred		0.65		Gain of phosphorylation at I261 (P = 0.0119);
MVP		0.63
MPC		0.99
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.42
gMVP		0.87

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: rs1347706857; hg19: chr7-102097968;