rs111033830

Positions:

• chr9-34648343-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong

The NM_000155.4(GALT):​c.574A>G​(p.Ser192Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S192N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.56

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 12 ACMG points.

• PS1: Transcript NM_000155.4 (GALT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr9-34648344-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 25220.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALT	NM_000155.4	c.574A>G	p.Ser192Gly	missense_variant	7/11	ENST00000378842.8
GALT	NM_001258332.2	c.247A>G	p.Ser83Gly	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALT	ENST00000378842.8	c.574A>G	p.Ser192Gly	missense_variant	7/11	1	NM_000155.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	.;D;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	3.1	.;M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.34	T;T;D
Polyphen		0.045	.;B;.
Vest4		0.84
MutPred		0.92		.;Loss of disorder (P = 0.1009);.;
MVP		0.98
MPC		0.76
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.78
gMVP		0.97

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: rs111033830; hg19: chr9-34648340;