rs61735984

chr9-34648117-C-Achr9-34648117-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_000155.4(GALT):c.510C>A(p.Ile170=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 1,614,188 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (12 hom.)
• Consequence: GALT NM_000155.4 splice_region, synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.86

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 9-34648117-C-A is Benign according to our data. Variant chr9-34648117-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281074.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=3, Uncertain_significance=1}. Variant chr9-34648117-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.87 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALT	NM_000155.4	c.510C>A	p.Ile170=	splice_region_variant, synonymous_variant	6/11	ENST00000378842.8
GALT	NM_001258332.2	c.183C>A	p.Ile61=	splice_region_variant, synonymous_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALT	ENST00000378842.8	c.510C>A	p.Ile170=	splice_region_variant, synonymous_variant	6/11	1	NM_000155.4	P1

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 426 AN: 152184 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0131

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00295 AC: 741 AN: 251494 Hom.: 4 AF XY: 0.00291 AC XY: 396 AN XY: 135920

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.00359

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00323 AC: 4725 AN: 1461886 Hom.: 12 Cov.: 33 AF XY: 0.00319 AC XY: 2317 AN XY: 727244

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.00347

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152302 Hom.: 2 Cov.: 32 AF XY: 0.00298 AC XY: 222 AN XY: 74460

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0131

Gnomad4 NFE AF: 0.00354

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00296 Hom.: 0

Bravo AF: 0.00195

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00421

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	GALT: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2020	This variant is associated with the following publications: (PMID: 27176039, 11919338) -

Galactosemia Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

May 30, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
Cadd	Benign	13
Dann	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61735984; hg19: chr9-34648114;