rs1338336697

Variant names:

• chrX-30691149-A-G
• rs1338336697
• NM_001205019.2:c.364A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001205019.2(GK):​c.364A>G​(p.Thr122Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000896 in 111,561 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.5e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GK NM_001205019.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97
• Publications: 0 publications found

Genes affected

GK (HGNC:4289): (glycerol kinase) The protein encoded by this gene belongs to the FGGY kinase family. This protein is a key enzyme in the regulation of glycerol uptake and metabolism. It catalyzes the phosphorylation of glycerol by ATP, yielding ADP and glycerol-3-phosphate. Mutations in this gene are associated with glycerol kinase deficiency (GKD). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

GK Gene-Disease associations (from GenCC):

• inborn glycerol kinase deficiency

  Inheritance: AR, XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GK	NM_001205019.2	c.364A>G	p.Thr122Ala	missense_variant	Exon 5 of 21	ENST00000427190.6	NP_001191948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GK	ENST00000427190.6	c.364A>G	p.Thr122Ala	missense_variant	Exon 5 of 21	5	NM_001205019.2	ENSP00000401720.2

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111561 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

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: AS_VQSR AF: 9.53e-7 AC: 1 AN: 1049786 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 328392

African (AFR) AF: 0.0000392 AC: 1 AN: 25518

American (AMR) AF: 0.00 AC: 0 AN: 35051

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19045

East Asian (EAS) AF: 0.00 AC: 0 AN: 29931

South Asian (SAS) AF: 0.00 AC: 0 AN: 52758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40471

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3502

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 799013

Other (OTH) AF: 0.00 AC: 0 AN: 44497

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111561 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33773

African (AFR) AF: 0.0000326 AC: 1 AN: 30691

American (AMR) AF: 0.00 AC: 0 AN: 10435

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3608

South Asian (SAS) AF: 0.00 AC: 0 AN: 2736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53157

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.364A>G (p.T122A) alteration is located in exon 5 (coding exon 5) of the GK gene. This alteration results from a A to G substitution at nucleotide position 364, causing the threonine (T) at amino acid position 122 to be replaced by an alanine (A). 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	0.19
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	.;.;T;.;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.3	M;M;M;M;.
PhyloP100		8.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.8	D;D;.;D;D
REVEL	Uncertain	0.58
Sift	Benign	0.075	T;T;.;T;D
Sift4G	Uncertain	0.026	D;D;D;D;T
Polyphen		1.0	.;D;.;D;.
Vest4		0.65
MutPred		0.53		Loss of disorder (P = 0.1592);Loss of disorder (P = 0.1592);Loss of disorder (P = 0.1592);Loss of disorder (P = 0.1592);.;
MVP		0.79
MPC		2.3
ClinPred		0.76	D
GERP RS		5.9
Varity_R		0.72
gMVP		0.79
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1338336697; hg19: chrX-30709266;