dbSNP rs75391579: GALT:p.Gln188Arg (chr9-34648170-A-G) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3PM1PP2PP3PP5

The NM_000155.4(GALT):c.563A>G(p.Gln188Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00254 in 1,614,168 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000538030: Multiple functional studies have demonstrated this variant causes reduced enzymatic activity of galactose-1-phosphate uridyltransferase (Reichardt et al., 1991" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q188K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 3 hom. )

Consequence

GALT
NM_000155.4 missense, splice_region

Scores

Splicing: ADA: 0.9958

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:39U:2O:1

Conservation

PhyloP100: 6.04

Publications

217 publications found

Variant links:

Genes affected

GALT (HGNC:4135): (galactose-1-phosphate uridylyltransferase) Galactose-1-phosphate uridyl transferase (GALT) catalyzes the second step of the Leloir pathway of galactose metabolism, namely the conversion of UDP-glucose + galactose-1-phosphate to glucose-1-phosphate + UDP-galactose. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

GALT Gene-Disease associations (from GenCC):

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

GALT links:

ENSG00000258728 (HGNC:):

ENSG00000258728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000538030: Multiple functional studies have demonstrated this variant causes reduced enzymatic activity of galactose-1-phosphate uridyltransferase (Reichardt et al., 1991; Elsas et al., 1994; Lai et al., 1999).; SCV000603785: Functional characterization of the variant protein indicates a significantly reduced enzymatic activity compared to wildtype (Reichardt 1991, Elsas 1994, Elsevier 1996, Lai 1999, Riehman 2001, Coelho 2014), and increased thermal instability (Elsevier 1996, Coelho 2014). PMID: 25614870. PMID: 8198125. PMID: 8943248. PMID: 10037750. PMID: 1897530. PMID: 11152465. PMID: 25592817.; SCV000631394: Experimental studies have shown that this missense change affects GALT function (PMID: 7887417, 9772178, 11152465, 25614870).; SCV002767218: "This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant causes reduced enzyme activity (PMID: 2011574)."; SCV004014680: Functional studies suggest that the presence of the p.Gln188Arg variant results in a reduced ability to form the GALT-UMP intermediate (PMID: 10037750; PMID: 27005423). Expression of the variant in COS cells followed by enzyme activity assays showed 10% of wild-type activity, which may be due to protein misfolding and increased proteolysis as suggested by mass spectrometry studies (PMID: 1897530; PMID: 27005423).; SCV004101381: Well-established in vitro functional studies of this variant strongly suggest a deleterious effect to the protein that is sufficient to be disease-causing (Reichardt et al, 1991).; SCV006070579: Published functional studies demonstrate Q188R results in significantly diminished GALT enzyme activity (Coelho AI, et al., 2014).; SCV000238870: Published functional studies demonstrate Q188R results in significantly diminished GALT enzyme activity (PMID: 1897530).; SCV006325202: Functional studies indicate that the p.Gln188Arg sequence change results in significantly reduced galctosidase activity versus wild-type GALT (PMID: 1897530, 27005423, 10037750).; SCV000966889: Many established functional assays have demonstrated reduced protein function of less than 1% due to the p.Gln188Arg allele (Reichardt 1991, Elsas 1995, Geeganage 1998, Tyfield 1999, Lai 1999, Riehman 2001, Coelho 2014, McCorvie 2016).; SCV004108100: The p.Gln188 residue forms part of the GALT enzyme active site, and in multiple functional studies the p.Gln188Arg substitution has been reported to nearly abolish GALT enzyme activity (e.g., Riehman et al. 2001. PubMed ID: 11152465; Coelho et al. 2014. PubMed ID: 25614870; McCorvie et al. 2016. PubMed ID: 27005423).; SCV004873728: Functional analysis showed ~15% of enzyme function when the p.Q188R alteration is in a heterozygous state and <1% when in a homozygous state (Elsevier, 1996; Viggiano, 2015).

PM1

In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000155.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 104 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 0.91493 (below the threshold of 3.09). Trascript score misZ: 1.8645 (below the threshold of 3.09). GenCC associations: The gene is linked to galactosemia, classic galactosemia.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 9-34648170-A-G is Pathogenic according to our data. Variant chr9-34648170-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3614.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000155.4. 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
	GALT	NM_000155.4	MANE Select	c.563A>G	p.Gln188Arg	missense splice_region	Exon 6 of 11	NP_000146.2
	GALT	NM_001258332.2		c.236A>G	p.Gln79Arg	missense splice_region	Exon 4 of 9	NP_001245261.1	P07902-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GALT	ENST00000378842.8	TSL:1 MANE Select	c.563A>G	p.Gln188Arg	missense splice_region	Exon 6 of 11	ENSP00000368119.4	P07902-1
ENSG00000258728	ENST00000556278.1	TSL:5	c.308A>G	p.Gln103Arg	missense splice_region	Exon 3 of 8	ENSP00000451792.1	G3V4G9
GALT	ENST00000902340.1		c.602A>G	p.Gln201Arg	missense splice_region	Exon 5 of 10	ENSP00000572399.1

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

284

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00325

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00143

AC:

360

AN:

251466

AF XY:

0.00146

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.000809

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00266

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.00261

AC:

3817

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

1820

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33480

American (AMR)

AF:

0.000783

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000591

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00320

AC:

3558

AN:

1112010

Other (OTH)

AF:

0.00242

AC:

146

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

252

505

757

1010

1262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<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:

0.00187

AC:

285

AN:

152312

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41570

American (AMR)

AF:

0.00124

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00325

AC:

221

AN:

68018

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.00240

Hom.:

Bravo

AF:

0.00195

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00132

AC:

160

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00273

EpiControl

AF:

0.00237

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase (29)

not provided (8)

Galactosemia (3)

GALT-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.27

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.9

PhyloP100

6.0

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.027

Polyphen

1.0

Vest4

0.97

MVP

1.0

MPC

1.9

ClinPred

0.73

GERP RS

4.8

Varity_R

0.99

gMVP

1.0

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

Splicevardb

2.0

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.32

Position offset: 1

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