9-34650449-A-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000155.4(GALT):c.1140A>C(p.Ter380CysextTer49) variant causes a stop lost change. The variant allele was found at a frequency of 0.00000342 in 1,461,636 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. *380*) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
GALT
NM_000155.4 stop_lost
NM_000155.4 stop_lost
Scores
1
3
3
Clinical Significance
Conservation
PhyloP100: 4.06
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 10 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 9-34650449-A-C is Pathogenic according to our data. Variant chr9-34650449-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25336.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.1140A>C | p.Ter380CysextTer49 | stop_lost | 11/11 | ENST00000378842.8 | |
GALT | NM_001258332.2 | c.813A>C | p.Ter271CysextTer49 | stop_lost | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALT | ENST00000378842.8 | c.1140A>C | p.Ter380CysextTer49 | stop_lost | 11/11 | 1 | NM_000155.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461636Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727152
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727152
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GnomAD4 genome ? Cov.: 32
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32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 21, 2023 | This sequence change disrupts the translational stop signal of the GALT mRNA. It is expected to extend the length of the GALT protein by 49 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This protein extension has been observed in individual(s) with galactosemia (PMID: 15841485, 28065439). ClinVar contains an entry for this variant (Variation ID: 25336). This variant results in an extension of the GALT protein. Other variant(s) that result in a similarly extended protein product (p.*380Argext*49) have been determined to be pathogenic (PMID: 10649501, 15633893, 20213376, 34030713). This suggests that these extensions are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 22, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
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