9-34649535-C-T

Position:

• chr9-34649535-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000155.4(GALT):​c.1030C>T​(p.Gln344*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,874 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 (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GALT NM_000155.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.13

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 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-34649535-C-T is Pathogenic according to our data. Variant chr9-34649535-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 834891.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALT	NM_000155.4	c.1030C>T	p.Gln344*	stop_gained	10/11	ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2	c.703C>T	p.Gln235*	stop_gained	8/9		NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8	c.1030C>T	p.Gln344*	stop_gained	10/11	1	NM_000155.4	ENSP00000368119.4
ENSG00000258728	ENST00000556278.1	c.432+1079C>T		intron_variant		5		ENSP00000451792.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the GALT protein. Other variant(s) that disrupt this region (p.Thr350Profs*9) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This sequence change results in a premature translational stop signal in the GALT gene (p.Gln344*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acids of the GALT protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with galactosemia (PMID: 22944367). ClinVar contains an entry for this variant (Variation ID: 834891). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.96
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: 29

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

Publications

LitVar

Other links and lift over

dbSNP: rs111033814; hg19: chr9-34649532;