rs80084721

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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). Synonymous variant affecting the same amino acid position (i.e. A198A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 29 hom. )

Consequence

GALK1
NM_000154.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:2

Conservation

PhyloP100: 9.56

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Uncertain_significance=3, Likely_benign=2}.

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	UniProt
GALK1	NM_000154.2 linkuse as main transcript	c.593C>T	p.Ala198Val	missense_variant	4/8	ENST00000588479.6
GALK1	NM_001381985.1 linkuse as main transcript	c.593C>T	p.Ala198Val	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALK1	ENST00000588479.6 linkuse as main transcript	c.593C>T	p.Ala198Val	missense_variant	4/8	1	NM_000154.2	P1

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00116

AC XY:

157

AN XY:

135500

show subpopulations

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.:

Cov.:

AF XY:

0.00103

AC XY:

752

AN XY:

726666

show subpopulations

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:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74488

show subpopulations

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.:

Bravo

AF:

0.000737

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00118

AC:

143

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of galactokinase

Pathogenic:1Uncertain:4Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2001	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 20, 2017	- -

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

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;.;D

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

.;D;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.028

MutationAssessor

Uncertain

2.6

M;.;M

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.54

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over