chr9-34647247-G-C

Position:

• chr9-34647247-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_000155.4(GALT):​c.241G>C​(p.Ala81Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,780 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A81T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.20

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84
• PP5: Variant 9-34647247-G-C is Pathogenic according to our data. Variant chr9-34647247-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1330596.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALT	NM_000155.4	c.241G>C	p.Ala81Pro	missense_variant	2/11	ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2	c.39G>C	p.Glu13Asp	missense_variant	2/9		NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8	c.241G>C	p.Ala81Pro	missense_variant	2/11	1	NM_000155.4	ENSP00000368119.4
ENSG00000258728	ENST00000556278.1	c.241G>C	p.Ala81Pro	missense_variant	2/8	5		ENSP00000451792.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251164 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461780 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727176

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 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	Jun 23, 2021	The GALT c.241G>C; p.Ala81Pro variant (rs111033665) is reported to be in compound heterozygous state with a pathogenic GALT variant p.Gln188Arg in the literature in an individual affected with mild galactosemia (Ohlsson 2019). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 81 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.761). Additionally, another variant at this codon (c.241G>A; p.Ala81Thr) has been reported in individuals with galactosemia. Based on available information, the p.Ala81Pro variant is considered to be likely pathogenic. References: Ohlsson A et al. Heterogeneity of disease-causing variants in the Swedish galactosemia population: Identification of 16 novel GALT variants. J Inherit Metab Dis. 2019 Sep;42(5):1008-1018. PMID: 31194895. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2023	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 81 of the GALT protein (p.Ala81Pro). This variant is present in population databases (rs111033665, gnomAD 0.002%). This missense change has been observed in individual(s) with galactose-1-phosphate uridylyltransferase deficiency (PMID: 31194895). 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: 1330596). 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. This variant disrupts the p.Ala81 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1427861). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 25, 2023

PP3, PM2_moderate, PM3_supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Pathogenic	1.3	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.6	N;N
REVEL	Pathogenic	0.76
Sift	Benign	0.28	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.041	B;.
Vest4		0.69
MutPred		0.68		Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);
MVP		0.99
MPC		1.1
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs111033665; hg19: chr9-34647244;