rs111033715
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000155.4(GALT):āc.512T>Cā(p.Phe171Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,614,042 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 (ā ā ).
Frequency
Genomes: š 0.000033 ( 0 hom., cov: 32)
Exomes š: 0.0000041 ( 0 hom. )
Consequence
GALT
NM_000155.4 missense
NM_000155.4 missense
Scores
15
2
1
Clinical Significance
Conservation
PhyloP100: 5.03
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000155.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 9-34648119-T-C is Pathogenic according to our data. Variant chr9-34648119-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALT | NM_000155.4 | c.512T>C | p.Phe171Ser | missense_variant | 6/11 | ENST00000378842.8 | |
GALT | NM_001258332.2 | c.185T>C | p.Phe62Ser | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALT | ENST00000378842.8 | c.512T>C | p.Phe171Ser | missense_variant | 6/11 | 1 | NM_000155.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251496Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135922
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461888Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727246
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74326
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:7
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 23, 1992 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 22, 2016 | Variant summary: The GALT c.512T>C (p.Phe171Ser) variant is located in the Galactose-1-phosphate uridyl transferase, N-terminal domain causing a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121466, which does not exceed the estimated maximal expected allele frequency for a pathogenic GALT variant of 1/346. Multiple publications cite the variant in affected individuals as homozygous or compound heterozygous, along with multiple clinical diagnostic laboratories citing the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 30, 2023 | The GALT c.512T>C; p.Phe171Ser variant (rs111033715) is described in several studies to have reduced or a complete loss of enzymatic activity (Crews 2000, McCorvie 2013, Reichardt 1992, Riehman 2001, Wang 1998). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3616). It is found in the general African American population with a low allele frequency of 0.02% (5/24016 alleles) in the Genome Aggregation Database. The phenylalanine at codon 171 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.985). Based on available information, this variant is considered to be pathogenic. References: Crews C et al. Functional consequence of substitutions at residue 171 in human galactose-1-phosphate uridylyltransferase. J Biol Chem. 2000 Jul 28;275(30):22847-53. PMID: 10811638 McCorvie TJ et al. Misfolding of galactose 1-phosphate uridylyltransferase can result in type I galactosemia. Biochim Biophys Acta. 2013 Aug;1832(8):1279-93. PMID: 23583749 Reichardt JK et al. Molecular characterization of two galactosemia mutations and one polymorphism: implications for structure-function analysis of human galactose-1-phosphate uridyltransferase. Biochemistry. 1992 Jun 23;31(24):5430-3. PMID: 1610789 Riehman K et al. Relationship between genotype, activity, and galactose sensitivity in yeast expressing patient alleles of human galactose-1-phosphate uridylyltransferase. J Biol Chem. 2001 Apr 6;276(14):10634-40. PMID: 11152465 Wang BB et al. Molecular and biochemical basis of galactosemia. Mol Genet Metab. 1998 Apr;63(4):263-9. PMID: 9635294 - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 171 of the GALT protein (p.Phe171Ser). This variant is present in population databases (rs111033715, gnomAD 0.02%). This missense change has been observed in individual(s) with galactosemia (PMID: 1610789, 18956253, 22944367, 23022339, 27176039). ClinVar contains an entry for this variant (Variation ID: 3616). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALT function (PMID: 1610789, 10811638, 23583749). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 15, 2019 | NM_000155.3(GALT):c.512T>C(F171S) is classified as likely pathogenic in the context of galactosemia. Sources cited for classification include the following: PMID 23583749, 23022339, 22944367, 10811638, 10960497, 11152465 and 1610789. Classification of NM_000155.3(GALT):c.512T>C(F171S) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses and is very rare or not present in genetic databases of healthy individuals. Please note: this variant was assessed in the context of healthy population screening. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 14, 2023 | PP3, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 25, 2020 | Published functional studies demonstrate a significant decrease in GALT enzyme activity (McCorvie et al., 2013; Crews et al., 2000; Riehman et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9635294, 18956253, 23022339, 1301925, 10408771, 10535394, 11397328, 22944367, 1610789, 25124065, 22975760, 11152465, 27176039, 20008339, 10811638, 23583749, 8198125) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 13, 2018 | - - |
Galactosemia Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 17, 2023 | The p.Phe171Ser variant in GALT has been reported in the homozygous state in at least 2 individuals and in the compound heterozygous state with another disease causing variant in in GALT in 6 individuals with galactosemia (Reichardt 1992 PMID: 1610789, Palmieri 1999 PMID: 10535394, Velazquez-Aragon 2008 PMID: 18956253, Singh 2012 PMID: 23022339, Boutron 2012 PMID: 22944367, Garcia 2016 PMID: 27176039). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 3616) and has been identified in 0.01% (5/41434) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In vitro functional studies provide evidence that this variant retains no enzymatic activity (Crews 2000 PMID: 10811638, McCorvie 2013 PMID: 23583749, Riehman 2001 PMID: 11152465) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive galactosemia. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PP3, PM2_Supporting, PP4. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;T
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;D;.
Vest4
MutPred
0.98
.;Gain of disorder (P = 0.019);.;
MVP
MPC
2.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at