rs111033695

Positions:

• chr9-34647879-T-A
• chr9-34647879-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000155.4(GALT):​c.425T>A​(p.Met142Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,614,190 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M142V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.10

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 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr9-34647878-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2573375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 9-34647879-T-A is Pathogenic according to our data. Variant chr9-34647879-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 3609.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.425T>A	p.Met142Lys	missense_variant	5/11	ENST00000378842.8
GALT	NM_001258332.2	c.98T>A	p.Met33Lys	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALT	ENST00000378842.8	c.425T>A	p.Met142Lys	missense_variant	5/11	1	NM_000155.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251496 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135922

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: 0.0000439

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13 AN XY: 727246

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: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1991	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 29, 2023	This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 142 of the GALT protein (p.Met142Lys). This variant is present in population databases (rs111033695, gnomAD 0.004%). This missense change has been observed in individual(s) with galactosemia (PMID: 2011574, 10384398, 10960497, 17041746, 20213376, 22944367, 23924834). ClinVar contains an entry for this variant (Variation ID: 3609). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 23, 2021	Variant summary: GALT c.425T>A (p.Met142Lys) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251496 control chromosomes. c.425T>A has been reported in the literature in multiple individuals affected with Galactosemia, both in the homozygous and compound heterozygous state (Reichardt_1991, Shin_1999, Milankovics_2010, Seyrantepe_1999, Bosch_2005, Gort_2006, Boutron_2012, etc). The variant has been reported to have <10% wild-type enzyme activity when expressed in COS cells (Reichardt_1991). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2022	Expression of M142K in COS cells was associated with a severe reduction in galactose-1-phosphate uridyltransferase (GALT) enzyme activity compared to wild type (Reichardt et al. 1991); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22944367, 17041746, 20008339, 10960497, 20213376, 31194252, 31980526, 34030713, 31589614, 10384398, 2011574) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	GALT: PM3:Very Strong, PM1, PM2, PM5, PP3, PS3:Supporting -

GALT-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 24, 2022

The GALT c.425T>A variant is predicted to result in the amino acid substitution p.Met142Lys. This variant has previously been reported in the homozygous state or with a second pathogenic GALT variant in multiple patients with classic galactosemia (e.g., Reichardt et al. 1991. PubMed ID 2011574; Shin et al. 1999. PubMed ID 10384398; Boutron et al. 2012, PMID 22944367). The p.Met142Lys substitution was reported to abolish GALT enzyme activity in a functional study using COS cells (Reichardt et al. 1991. PubMed ID 2011574). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-34647876-T-A). It is interpreted as a pathogenic variant but multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3609/). Taken together, we interpret this variant as pathogenic. -

Galactosemia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.96
MutPred		0.93		.;Gain of catalytic residue at M142 (P = 0.0016);
MVP		1.0
MPC		1.4
ClinPred		0.90	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs111033695; hg19: chr9-34647876;