rs149825190

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000154.2(GALK1):c.746C>T(p.Ala249Val) variant causes a missense change. The variant allele was found at a frequency of 0.000574 in 1,613,720 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A249T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00057 ( 2 hom. )

Consequence

GALK1
NM_000154.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 3.68

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

galactokinase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Myriad Women’s Health, Orphanet

GALK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014584869).

BP6

Variant 17-75762751-G-A is Benign according to our data. Variant chr17-75762751-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 325232.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000644 (98/152158) while in subpopulation AMR AF = 0.00242 (37/15274). AF 95% confidence interval is 0.00181. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000154.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALK1	NM_000154.2	MANE Select	c.746C>T	p.Ala249Val	missense	Exon 5 of 8	NP_000145.1	P51570
	GALK1	NM_001381985.1		c.746C>T	p.Ala249Val	missense	Exon 5 of 9	NP_001368914.1	P51570

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GALK1	ENST00000588479.6	TSL:1 MANE Select	c.746C>T	p.Ala249Val	missense	Exon 5 of 8	ENSP00000465930.1	P51570
GALK1	ENST00000864472.1		c.746C>T	p.Ala249Val	missense	Exon 5 of 9	ENSP00000534531.1
GALK1	ENST00000864469.1		c.746C>T	p.Ala249Val	missense	Exon 5 of 9	ENSP00000534528.1

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000737

AC:

185

AN:

251030

AF XY:

0.000663

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.00467

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000573

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000567

AC:

828

AN:

1461562

Hom.:

Cov.:

AF XY:

0.000519

AC XY:

377

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.00210

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00455

AC:

119

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000151

AC:

AN:

53112

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000492

AC:

547

AN:

1112000

Other (OTH)

AF:

0.000844

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

105

157

210

262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000644

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41424

American (AMR)

AF:

0.00242

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68034

Other (OTH)

AF:

0.00144

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000652

Hom.:

Bravo

AF:

0.000669

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000560

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of galactokinase (4)

GALK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.25

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.073

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.050

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.99

PhyloP100

3.7

PrimateAI

Benign

0.44

PROVEAN

Benign

0.82

REVEL

Benign

0.21

Sift

Benign

1.0

Sift4G

Benign

0.51

Polyphen

0.50

Vest4

0.27

MVP

0.86

MPC

0.16

ClinPred

0.036

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.22

Mutation Taster

=72/28

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over