chrX-30668094-A-C

Variant names:

• chrX-30668094-A-C
• NM_001205019.2:c.235A>C

Variant summary

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

The NM_001205019.2(GK):​c.235A>C​(p.Asn79His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000027 (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: 8.87
• 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, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GK	NM_001205019.2	c.235A>C	p.Asn79His	missense_variant	Exon 3 of 21	ENST00000427190.6	NP_001191948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GK	ENST00000427190.6	c.235A>C	p.Asn79His	missense_variant	Exon 3 of 21	5	NM_001205019.2	ENSP00000401720.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000269 AC: 25 AN: 928240 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 262774

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000858 AC: 2 AN: 23302

American (AMR) AF: 0.00 AC: 0 AN: 35000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18305

East Asian (EAS) AF: 0.00 AC: 0 AN: 29493

South Asian (SAS) AF: 0.0000197 AC: 1 AN: 50695

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40473

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3691

European-Non Finnish (NFE) AF: 0.0000306 AC: 21 AN: 686741

Other (OTH) AF: 0.0000247 AC: 1 AN: 40540

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

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.235A>C (p.N79H) alteration is located in exon 3 (coding exon 3) of the GK gene. This alteration results from a A to C substitution at nucleotide position 235, causing the asparagine (N) at amino acid position 79 to be replaced by a histidine (H). 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	0.092
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;.;T;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.7	L;L;L;L;.
PhyloP100		8.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N;N;.;N;N
REVEL	Benign	0.28
Sift	Benign	0.040	D;D;.;D;D
Sift4G	Uncertain	0.033	D;D;D;D;T
Polyphen		0.0020	.;B;.;B;.
Vest4		0.67
MutPred		0.38		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.80
MPC		1.1
ClinPred		0.93	D
GERP RS		5.6
Varity_R		0.62
gMVP		0.63
Mutation Taster		=243/57	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

hg19: chrX-30686211;