9-34646575-CCAGTCAGT-CCAGT

Variant names:

• chr9-34646575-CCAGT-C
• rs111033640
• ENST00000902339.1:c.-119_-116delGTCA

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 5P and 8B. PS3 PP5 BA1

The ENST00000450095.6(GALT):​c.-321_-318delGTCA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0587 in 1,216,800 control chromosomes in the GnomAD database, including 2,445 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars). ClinVar reports functional evidence for this variant: "SCV000959727: Experimental studies have shown that this variant affects GALT function (PMID:11286503, 11479743, 19224951)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.047 (259 hom., cov: 31)
  • Exomes 𝑓: 0.060 (2186 hom.)
• Consequence: GALT ENST00000450095.6 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:14 U:1 B:1 O:1
• Conservation: PhyloP100: 0.263
• Publications: 18 publications found

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]

GALT Gene-Disease associations (from GenCC):

• classic galactosemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• galactosemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health

ENSG00000294190 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000959727: Experimental studies have shown that this variant affects GALT function (PMID: 11286503, 11479743, 19224951).; SCV002506107: Functional characterization of the complex variant indicates a reduction in mRNA transcription due to the deletion in the promoter region (Elsas 2001, Trbusek 2001).; SCV006059859: Elsas et al. (2001) and Trbusek et al. (2001) demonstrated that the c.-119_-116delGTCA variant confers reduced promoter activity to transfected cell lines and also showed that human lymphoblasts derived from patients with the Duarte allele have reduced GALT mRNA, leading to reduced GALT activity.; SCV000238877: The c.-119_-116delGTCA promoter variant (Duarte 2 variant) causes a reduction in GALT transcription resulting in approximately 50% of normal galactose-1-phosphate uridyltransferase (GALT) activity in individuals who are homozygous for this allele (PMID: 15841485, 19224951, 9012409); SCV004873726: Functional studies have shown that this deletion decreases GALT mRNA production and enzyme activity (Kozák, 1999; Elsas, 2001; Trbusek, 2001; Carney, 2009).
• PP5: Variant 9-34646575-CCAGT-C is Pathogenic according to our data. Variant chr9-34646575-CCAGT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity|other. ClinVar VariationId is 25111.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0629 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000450095.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALT	NM_000155.4	MANE Select	c.-129_-126delCAGT		upstream_gene	N/A	NP_000146.2
	GALT	NM_001258332.2		c.-331_-328delCAGT		upstream_gene	N/A	NP_001245261.1	P07902-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALT	ENST00000902339.1		c.-119_-116delGTCA		5_prime_UTR	Exon 1 of 10	ENSP00000572398.1
	GALT	ENST00000902334.1		c.-119_-116delGTCA		5_prime_UTR	Exon 1 of 10	ENSP00000572393.1
	GALT	ENST00000902335.1		c.-119_-116delGTCA		5_prime_UTR	Exon 1 of 10	ENSP00000572394.1

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 7161 AN: 152148 Hom.: 258 Cov.: 31

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.0490

Gnomad ASJ AF: 0.0481

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.0690

Gnomad FIN AF: 0.0672

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0645

Gnomad OTH AF: 0.0440

GnomAD4 exome AF: 0.0603 AC: 64222 AN: 1064534 Hom.: 2186 AF XY: 0.0610 AC XY: 33204 AN XY: 544444

African (AFR) AF: 0.0111 AC: 282 AN: 25412

American (AMR) AF: 0.0491 AC: 1954 AN: 39776

Ashkenazi Jewish (ASJ) AF: 0.0510 AC: 1186 AN: 23264

East Asian (EAS) AF: 0.00640 AC: 231 AN: 36070

South Asian (SAS) AF: 0.0758 AC: 5779 AN: 76230

European-Finnish (FIN) AF: 0.0679 AC: 3421 AN: 50410

Middle Eastern (MID) AF: 0.0472 AC: 162 AN: 3432

European-Non Finnish (NFE) AF: 0.0636 AC: 48525 AN: 762866

Other (OTH) AF: 0.0570 AC: 2682 AN: 47074

GnomAD4 genome AF: 0.0470 AC: 7163 AN: 152266 Hom.: 259 Cov.: 31 AF XY: 0.0468 AC XY: 3488 AN XY: 74466

African (AFR) AF: 0.0124 AC: 515 AN: 41560

American (AMR) AF: 0.0491 AC: 751 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0481 AC: 167 AN: 3472

East Asian (EAS) AF: 0.00926 AC: 48 AN: 5182

South Asian (SAS) AF: 0.0689 AC: 332 AN: 4820

European-Finnish (FIN) AF: 0.0672 AC: 713 AN: 10608

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0645 AC: 4384 AN: 67998

Other (OTH) AF: 0.0445 AC: 94 AN: 2114

Alfa AF: 0.0553 Hom.: 30

Bravo AF: 0.0422

Asia WGS AF: 0.0340 AC: 118 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; other

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	-	1	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase (7)
4	-	-	not provided (5)
2	-	-	Galactosemia (2)
1	-	-	Classical galactosemia, homozygous Duarte-type (1)
1	-	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.26

Splicing

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

Other links and lift over

dbSNP: rs111033640; hg19: chr9-34646572;