chr17-75763032-G-A

Position:

• chr17-75763032-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000154.2(GALK1):​c.593C>T​(p.Ala198Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000987 in 1,612,946 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (29 hom.)
• Consequence: GALK1 NM_000154.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:2
• Conservation: PhyloP100: 9.56

Genes affected

GALK1 (HGNC:4118): (galactokinase 1) Galactokinase is a major enzyme for the metabolism of galactose and its deficiency causes congenital cataracts during infancy and presenile cataracts in the adult population. [provided by RefSeq, Jul 2008]

GALK1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011396736).
• BP6: Variant 17-75763032-G-A is Benign according to our data. Variant chr17-75763032-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5633.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000637 (97/152334) while in subpopulation EAS AF= 0.0147 (76/5182). AF 95% confidence interval is 0.012. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALK1	NM_000154.2	c.593C>T	p.Ala198Val	missense_variant	4/8	ENST00000588479.6	NP_000145.1
GALK1	NM_001381985.1	c.593C>T	p.Ala198Val	missense_variant	4/9		NP_001368914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALK1	ENST00000588479.6	c.593C>T	p.Ala198Val	missense_variant	4/8	1	NM_000154.2	ENSP00000465930.1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00124 AC: 311 AN: 250192 Hom.: 2 AF XY: 0.00116 AC XY: 157 AN XY: 135500

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0150

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00102 AC: 1495 AN: 1460612 Hom.: 29 Cov.: 50 AF XY: 0.00103 AC XY: 752 AN XY: 726666

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0323

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000712 AC XY: 53 AN XY: 74488

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0147

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000856 Hom.: 2

Bravo AF: 0.000737

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00118 AC: 143

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of galactokinase Pathogenic:1 Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 07, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 198 of the GALK1 protein (p.Ala198Val). This variant is present in population databases (rs80084721, gnomAD 1.5%). This missense change has been observed in individual(s) with mild galactokinase deficiency and/or bilateral cataracts (PMID: 11231902). It has also been observed to segregate with disease in related individuals. This variant is also known as Osaka variant. ClinVar contains an entry for this variant (Variation ID: 5633). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects GALK1 function (PMID: 11231902, 12694189). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2001	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 20, 2017	- -

GALK1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2024

The GALK1 c.593C>T variant is predicted to result in the amino acid substitution p.Ala198Val. This variant, also known as the Osaka variant, has been reported in mild galactokinase deficiency (GALK) in three families and segregated with disease (Okano et al. 2001. PubMed ID: 11231902). This study also found the variant had a much higher prevalence in Japanese and Korean populations and there was evidence of a correlation between the presence of the variant and development of age-related cataracts. It has also been reported in a patient with glycogen storage disease; however, it was considered to be a variant of uncertain significance for the disease (Fang et al. 2021. PubMed ID: 33763395). In vitro functional studies demonstrate reduced protein activity and impaired stability (Okano et al. 2001. PubMed ID: 11231902; Timson et al. 2003. PubMed ID: 12694189). This variant is reported in 1.5% of alleles in individuals of East Asian descent in gnomAD, including 2 homozygotes. It has conflicting interpretations ranging from likely benign to pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/5633/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 05, 2022

Variant summary: GALK1 c.593C>T (p.Ala198Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 250192 control chromosomes, predominantly at a frequency of 0.015 within the East Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 13-fold of the estimated maximal expected allele frequency (MPAF) for a pathogenic variant in GALK1 causing Deficiency of Galactokinase phenotype (0.0011). However, the variant was reported in certain East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.044-0.047 (in the HGVD-Kyoto and jMorp databases). This frequency is about 40-fold higher than the of the MPAF (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.593C>T (aka. Osaka variant), was found in 4 compound heterozygous Japanese newborns with decreased GALK activity, and all of them carried a (presumed) null variant in trans, however, none of these cases had cataract or other clinical manifestations during the neonatal period (Okano_2001). The authors of this study also performed a population analysis, which revealed that the prevalence of A198V is 4.1% in Japanese and 2.8% in Koreans, with a lower incidence in Taiwanese and Chinese, and no incidence in blacks or whites from the United States. On the other hand, authors found that the variant had a significantly higher frequency (7.8%) in Japanese adults (>55 years of age) with bilateral cataract, therefore the Osaka variant might be one of the genetic risk factors in age-related cataract formation (Okano_2001). To our knowledge, the variant has not been reported in the literature in individuals affected with congenital, neonatal, or early childhood bilateral cataracts that seems to be the only consistent manifestation in patients with classic GALK1 deficiency (Rubio-Gozalbo_2021). Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that while the variant protein had normal Km, the in vivo activity in patient derived samples was about 20% of the normal, which corresponded to the decreased amount and activity for the variant protein expressed in mammalian cells, suggesting a decreased stability for the variant protein (Okano_2001). However, the variant protein was found to have a normal expression and activity (Vmax and Km) in a bacterial expression system (Timson_2003). These data suggest that the variant may result in an increased degradation in human (mammalian) cells (Timson_2003). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=4) or likely benign (n=1). Based on the evidence outlined above, the although the variant might represent a risk-factor for age-related cataract formation, it is unlikely to be associated with congenital cataracts, therefore the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	.;D;D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Uncertain	0.028	D
MutationAssessor	Uncertain	2.6	M;.;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.3	D;.;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0030	D;.;.
Sift4G	Benign	0.091	T;T;T
Polyphen		0.90	P;.;P
Vest4		0.91
MVP		0.89
MPC		0.22
ClinPred		0.11	T
GERP RS		5.5
Varity_R		0.86
gMVP		0.86

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: rs80084721; hg19: chr17-73759113;