rs111033750

chr9-34648436-C-Achr9-34648436-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_000155.4(GALT):c.667C>A(p.Arg223Ser) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R223C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.14

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000155.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-34648437-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2910717.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 9-34648436-C-A is Pathogenic according to our data. Variant chr9-34648436-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1482501.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.667C>A	p.Arg223Ser	missense_variant	7/11	ENST00000378842.8
GALT	NM_001258332.2	c.340C>A	p.Arg114Ser	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALT	ENST00000378842.8	c.667C>A	p.Arg223Ser	missense_variant	7/11	1	NM_000155.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 223 of the GALT protein (p.Arg223Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with galactose-1-phosphate uridylyltransferase deficiency (PMID: 17876724). ClinVar contains an entry for this variant (Variation ID: 1482501). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALT function (PMID: 22461411). This variant disrupts the p.Arg223 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 29, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.018	A;A
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.044	D;D;D
Sift4G	Benign	0.41	T;T;T
Polyphen		0.17	.;B;.
Vest4		0.38
MVP		0.94
MPC		1.0
ClinPred		0.69	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.49
gMVP		0.81

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: rs111033750; hg19: chr9-34648433;