chr9-34648826-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000155.4(GALT):ā€‹c.752A>Cā€‹(p.Tyr251Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,432 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.000012 ( 0 hom. )

Consequence

GALT
NM_000155.4 missense

Scores

12
6
1

Clinical Significance

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

Conservation

PhyloP100: 1.96
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 9-34648826-A-C is Pathogenic according to our data. Variant chr9-34648826-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 25254.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GALTNM_000155.4 linkc.752A>C p.Tyr251Ser missense_variant 8/11 ENST00000378842.8 NP_000146.2 P07902-1B2RAT6A0A0S2Z3Y7
GALTNM_001258332.2 linkc.425A>C p.Tyr142Ser missense_variant 6/9 NP_001245261.1 P07902-2B2RAT6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GALTENST00000378842.8 linkc.752A>C p.Tyr251Ser missense_variant 8/111 NM_000155.4 ENSP00000368119.4 P07902-1
ENSG00000258728ENST00000556278.1 linkc.432+370A>C intron_variant 5 ENSP00000451792.1 G3V4G9

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461296
Hom.:
0
Cov.:
32
AF XY:
0.0000124
AC XY:
9
AN XY:
727026
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.0000153
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 31, 2021The GALT c.752A>C; p.Tyr251Ser variant (rs111033755) is reported in the literature in multiple individuals affected with galactosemia (Tyfield 1999, Yang 2002). This variant is also reported in ClinVar (Variation ID: 25254). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another variant at this codon (c.752A>G; p.Tyr251Cys) has been reported in individuals with galactosemia (Tyfield 1999). The tyrosine at codon 251 is weakly conserved, but computational analyses predict that this variant is deleterious (REVEL: 0.879). Based on available information, the p.Tyr251Ser variant is considered to be likely pathogenic. References: Tyfield L. Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat. 1999;13(6):417-30. PMID: 10408771. Yang YP, Corley N, Garcia-Heras J. Molecular analysis in newborns from Texas affected with galactosemia. Hum Mutat. 2002 Jan;19(1):82-3. PMID: 11754113. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 19, 2024Variant summary: GALT c.752A>C (p.Tyr251Ser) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, C-terminal domain (IPR005850) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250978 control chromosomes. c.752A>C has been reported in the literature in individuals affected with Galactosemia (Elsas_1998, Robertson_2000, Yang_2002). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11261429, 11397328, 11754113). ClinVar contains an entry for this variant (Variation ID: 25254). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 19, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.98
.;D
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.0
.;M
PrimateAI
Uncertain
0.49
T
PROVEAN
Pathogenic
-6.4
D;D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.031
D;D
Polyphen
0.85
.;P
Vest4
0.74
MutPred
0.97
.;Loss of sheet (P = 0.0817);
MVP
0.99
MPC
1.7
ClinPred
0.91
D
GERP RS
4.6
Varity_R
0.97
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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.

Other links and lift over

dbSNP: rs111033755; hg19: chr9-34648823; API