chr9-34648826-AC-CT

Position:

• chr9-34648826-AC-CT

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000155.4(GALT):​c.752_753delACinsCT​(p.Tyr251Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 1.96

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]

ENSG00000258728 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-34648826-AC-CT is Pathogenic according to our data. Variant chr9-34648826-AC-CT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286433.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALT	NM_000155.4	c.752_753delACinsCT	p.Tyr251Ser	missense_variant		ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2	c.425_426delACinsCT	p.Tyr142Ser	missense_variant			NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8	c.752_753delACinsCT	p.Tyr251Ser	missense_variant		1	NM_000155.4	ENSP00000368119.4
ENSG00000258728	ENST00000556278.1	c.432+370_432+371delACinsCT		intron_variant		5		ENSP00000451792.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 06, 2021	The GALT c.752_753delinsCT; p.Tyr251Ser variant (rs886043390), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 286433). However, other variants at this codon, including one resulting in the same amino acid change (c.752A>C; p.Tyr251Ser; c.752A>G; p.Tyr251Cys), have been reported in individuals with galactosemia (Elsas 1998, Robertson 2000, Shin 1999, Tyfield 1999, Yang 2002). The c.752_753delinsCT; p.Tyr251Ser variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The tyrosine at codon 251 is weakly conserved, but computational analyses predict that this variant is deleterious (REVEL: 0.975). Based on available information, this variant is considered to be likely pathogenic. References: Elsas LJ 2nd and Lai K. The molecular biology of galactosemia. Genet Med. 1998 Nov-Dec;1(1):40-8. PMID: 11261429. Robertson A et al. Outcomes analysis of verbal dyspraxia in classic galactosemia. Genet Med. 2000 Mar-Apr;2(2):142-8. PMID: 11397328. Shin YS et al. Molecular and biochemical basis for variants and deficiency forms of galactose-1-phosphate uridyltransferase. J Inherit Metab Dis. 1999 May;22(3):327-9. PMID: 10384398. Tyfield L et al. Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat. 1999;13(6):417-30. PMID: 10408771. Yang YP et al. Molecular analysis in newborns from Texas affected with galactosemia. Hum Mutat. 2002 Jan;19(1):82-3. PMID: 11754113. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 11, 2023	This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 251 of the GALT protein (p.Tyr251Ser). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with galactosemia (PMID: 11397328, 11754113; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 286433). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Tyr251 amino acid residue in GALT. Other variant(s) that disrupt this residue have been observed in individuals with GALT-related conditions (PMID: 10384398), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 22, 2016

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 22, 2024

Variant summary: GALT c.752_753delinsCT (p.Tyr251Ser) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, C-terminal (IPR005850) of the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 1613432 control chromosomes (gnomAD v4.0.0). This frequency is not significantly higher than estimated for a pathogenic variant in GALT causing Galactosemia (1.2e-05 vs 0.0029), allowing no conclusion about variant significance. c.752_753delinsCT has been reported in the literature in individuals affected with Galactosemia (Yang_2002, Robertson_2000). 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: 11397328, 11754113). ClinVar contains an entry for this variant (Variation ID: 286433). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886043390; hg19: chr9-34648823;