chr9-34648421-C-T

Position:

• chr9-34648421-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000155.4(GALT):​c.652C>T​(p.Leu218=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0337 in 1,614,124 control chromosomes in the GnomAD database, including 1,339 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (99 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1240 hom.)
• Consequence: GALT NM_000155.4 synonymous
• Clinical Significance: Benign; other criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 0.837

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 9-34648421-C-T is Benign according to our data. Variant chr9-34648421-C-T is described in ClinVar as [Benign, other]. Clinvar id is 39372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-34648421-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.837 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALT	NM_000155.4	c.652C>T	p.Leu218=	synonymous_variant	7/11	ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2	c.325C>T	p.Leu109=	synonymous_variant	5/9		NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8	c.652C>T	p.Leu218=	synonymous_variant	7/11	1	NM_000155.4	ENSP00000368119	P1

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4250 AN: 152144 Hom.: 100 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.0637

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0425

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0310

Gnomad OTH AF: 0.0354

GnomAD3 exomes AF: 0.0373 AC: 9391 AN: 251466 Hom.: 308 AF XY: 0.0415 AC XY: 5646 AN XY: 135910

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.0608

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.106

Gnomad FIN exome AF: 0.0401

Gnomad NFE exome AF: 0.0320

Gnomad OTH exome AF: 0.0384

GnomAD4 exome AF: 0.0343 AC: 50139 AN: 1461862 Hom.: 1240 Cov.: 33 AF XY: 0.0367 AC XY: 26696 AN XY: 727232

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.0175

Gnomad4 ASJ exome AF: 0.0623

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.0398

Gnomad4 NFE exome AF: 0.0301

Gnomad4 OTH exome AF: 0.0384

GnomAD4 genome AF: 0.0279 AC: 4248 AN: 152262 Hom.: 99 Cov.: 32 AF XY: 0.0292 AC XY: 2177 AN XY: 74446

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.0222

Gnomad4 ASJ AF: 0.0597

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.0425

Gnomad4 NFE AF: 0.0310

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0302 Hom.: 111

Bravo AF: 0.0233

Asia WGS AF: 0.0420 AC: 145 AN: 3478

EpiCase AF: 0.0382

EpiControl AF: 0.0356

ClinVar

Significance: Benign; other

Submissions summary: Benign:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Benign:7

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 19, 2021	- -
Benign, no assertion criteria provided	literature only	GeneReviews	Sep 23, 2014	- -

not provided Benign:3 Other:1

other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2015	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Galactosemia Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.0
DANN	Benign	0.82

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: rs2070075; hg19: chr9-34648418;