rs1554709099

Variant names:

• chr9-34646609-T-G
• rs1554709099
• ENST00000450095.6:c.-298T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000450095.6(GALT):​c.-298T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,370,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: GALT ENST00000450095.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.544
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• galactosemia

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

ENSG00000294190 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.19).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALT	NM_000155.4	c.-96T>G		upstream_gene_variant		ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2	c.-298T>G		upstream_gene_variant			NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8	c.-96T>G		upstream_gene_variant		1	NM_000155.4	ENSP00000368119.4
ENSG00000258728	ENST00000556278.1	c.-96T>G		upstream_gene_variant		5		ENSP00000451792.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1370436 Hom.: 0 Cov.: 22 AF XY: 0.00000146 AC XY: 1 AN XY: 686028

African (AFR) AF: 0.00 AC: 0 AN: 31536

American (AMR) AF: 0.00 AC: 0 AN: 43960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25458

East Asian (EAS) AF: 0.00 AC: 0 AN: 38998

South Asian (SAS) AF: 0.00 AC: 0 AN: 84014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4254

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1033590

Other (OTH) AF: 0.0000175 AC: 1 AN: 57094

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GALT c.-96T>G is located in the untranscribed region upstream of the GALT gene region. The variant was absent in 31388 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-96T>G has been reported in the literature as a compound heterozygous genotype together with a pathogenic variant in an individual affected with Galactosemia (Welling_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28065439, 31954591, 31845337). ClinVar contains an entry for this variant (Variation ID: 555856). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Dec 29, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Benign	0.97
PhyloP100		0.54
PromoterAI		-0.67	Under-expression

Splicing

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

Other links and lift over

dbSNP: rs1554709099; hg19: chr9-34646606;