rs111033711

Positions:

• chr9-34648085-CT-C

Variant summary

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

The NM_000155.4(GALT):​c.508-29delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GALT NM_000155.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 2.62

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 9-34648085-CT-C is Pathogenic according to our data. Variant chr9-34648085-CT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 25194.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALT	NM_000155.4	c.508-29delT		intron_variant		ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2	c.181-29delT		intron_variant			NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8	c.508-29delT		intron_variant		1	NM_000155.4	ENSP00000368119.4
ENSG00000258728	ENST00000556278.1	c.253-29delT		intron_variant		5		ENSP00000451792.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000896

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 25, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 28, 2021	This sequence change falls in intron 5 of the GALT gene. It does not directly change the encoded amino acid sequence of the GALT protein. It affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with classical galactosemia (PMID: 15841485; Invitae). ClinVar contains an entry for this variant (Variation ID: 25194). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

GALT-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 25, 2023

The GALT c.508-29delT variant is predicted to result in an intronic deletion. This variant was reported in a Somali individual with classic galactosemia, with the authors predicting it may affect a splicing branch point. However, no additional functional or segregation studies were performed to help clarify the pathogenicity of this variant (Bosch et al. 2005. PubMed ID: 15841485). It was also reported in the homozygous state in two additional Somalian galactosemia patients. Based on mRNA studies using fibroblasts from one of the homozygous individuals, the c.508-29delT variant led to the insertion of 66 bp of sequence from intron 5 and subsequent premature termination (See Table 1 and Supplemental Figure S1 in Ohlsson and Wedell. 2019. PubMed ID: 31194895; variant described as p.(Gln169_Ile170insTer20) in Table 1). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. Taken together, this variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

May 31, 2024

PP4, PM2, PM3, PS3_supporting, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.41		Position offset: 30

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

Publications

LitVar

Other links and lift over

dbSNP: rs111033711; hg19: chr9-34648082;