chr1-23797718-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP2PP3_ModeratePP5_Very_Strong

The NM_001008216.2(GALE):c.505C>T(p.Arg169Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000062 in 1,613,974 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

GALE
NM_001008216.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 4.50

Publications

11 publications found

Variant links:

Genes affected

GALE (HGNC:4116): (UDP-galactose-4-epimerase) This gene encodes UDP-galactose-4-epimerase which catalyzes two distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose, and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. The bifunctional nature of the enzyme has the important metabolic consequence that mutant cells (or individuals) are dependent not only on exogenous galactose, but also on exogenous N-acetylgalactosamine as a necessary precursor for the synthesis of glycoproteins and glycolipids. Mutations in this gene result in epimerase-deficiency galactosemia, also referred to as galactosemia type 3, a disease characterized by liver damage, early-onset cataracts, deafness and cognitive disability, with symptoms ranging from mild ('peripheral' form) to severe ('generalized' form). Multiple alternatively spliced transcripts encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

GALE Gene-Disease associations (from GenCC):

galactose epimerase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics

GALE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 9 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.32246 (below the threshold of 3.09). Trascript score misZ: 0.87424 (below the threshold of 3.09). GenCC associations: The gene is linked to galactose epimerase deficiency.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

PP5

Variant 1-23797718-G-A is Pathogenic according to our data. Variant chr1-23797718-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 21171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008216.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GALE	NM_001008216.2	MANE Select	c.505C>T	p.Arg169Trp	missense	Exon 6 of 12	NP_001008217.1
GALE	NM_000403.4		c.505C>T	p.Arg169Trp	missense	Exon 6 of 12	NP_000394.2
GALE	NM_001127621.2		c.505C>T	p.Arg169Trp	missense	Exon 5 of 11	NP_001121093.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GALE	ENST00000617979.5	TSL:1 MANE Select	c.505C>T	p.Arg169Trp	missense	Exon 6 of 12	ENSP00000483375.1
GALE	ENST00000374497.7	TSL:1	c.505C>T	p.Arg169Trp	missense	Exon 6 of 12	ENSP00000363621.3
GALE	ENST00000429356.5	TSL:5	c.313C>T	p.Arg105Trp	missense	Exon 4 of 8	ENSP00000398585.1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000716

AC:

AN:

251474

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000598

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000622

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000479

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000612

AC:

AN:

1111994

Other (OTH)

AF:

0.0000497

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000495

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

UDPglucose-4-epimerase deficiency (4)

UDPglucose-4-epimerase deficiency;C5935599:Thrombocytopenia 13, syndromic (2)

not provided (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.73

MutationAssessor

Pathogenic

3.2

PhyloP100

4.5

PrimateAI

Benign

0.27

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.77

MutPred

0.85

Gain of catalytic residue at R169 (P = 0.1633)

MVP

0.93

MPC

0.52

ClinPred

0.70

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.78

Mutation Taster

=17/83

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over