Variant rs111033608 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The ENST00000588479.6(GALK1):c.1144C>T(p.Gln382Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,612,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

GALK1
ENST00000588479.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.43

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 Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0297 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-75758091-G-A is Pathogenic according to our data. Variant chr17-75758091-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALK1	NM_000154.2 linkuse as main transcript	c.1144C>T	p.Gln382Ter	stop_gained	8/8	ENST00000588479.6	NP_000145.1
GALK1	NM_001381985.1 linkuse as main transcript	c.1144C>T	p.Gln382Ter	stop_gained	8/9		NP_001368914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALK1	ENST00000588479.6 linkuse as main transcript	c.1144C>T	p.Gln382Ter	stop_gained	8/8	1	NM_000154.2	ENSP00000465930	P1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000366

AC:

AN:

245624

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

133774

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1460012

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726292

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000853

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of galactokinase

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 12, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2022	This sequence change creates a premature translational stop signal (p.Gln382*) in the GALK1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the GALK1 protein. This variant is present in population databases (rs111033608, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with galactokinase galactosemia (PMID: 10790206). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Q832stop. ClinVar contains an entry for this variant (Variation ID: 5631). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects GALK1 function (PMID: 10790206). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 28, 2023	Variant summary: GALK1 c.1144C>T (p.Gln382X) is located within the last exon of the gene and while it is not expected to undergo nonsense mediated decay, it results in a premature termination codon and is predicted to cause a truncation of the encoded protein, a known mechanism for disease. The variant allele was found at a frequency of 3.7e-05 in 245624 control chromosomes, almost exclusively in the Latino/Admixed American subpopulation in the gnomAD database. c.1144C>T has been reported in the literature as a biallelic genotype in multiple individuals from Costa Rica affected with Deficiency Of Galactokinase (e.g. Kolosha_2000). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in approximately 10% of normal activity (Kolosha_2000). The following publication has been ascertained in the context of this evaluation (PMID: 10790206). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.78

MutationTaster

Benign

1.0

A;A;A

Vest4

0.075

GERP RS

3.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

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