rs2070074

Variant names:

• chr9-34649445-A-G
• rs2070074
• NM_000155.4:c.940A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000155.4(GALT):​c.940A>G​(p.Asn314Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0937 in 1,613,986 control chromosomes in the GnomAD database, including 8,067 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars).

• Frequency:
  • Genomes: 𝑓 0.075 (589 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7478 hom.)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:6 U:1 B:12 O:2
• Conservation: PhyloP100: 1.74

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015891492).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALT	NM_000155.4	c.940A>G	p.Asn314Asp	missense_variant	Exon 10 of 11	ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2	c.613A>G	p.Asn205Asp	missense_variant	Exon 8 of 9		NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8	c.940A>G	p.Asn314Asp	missense_variant	Exon 10 of 11	1	NM_000155.4	ENSP00000368119.4
ENSG00000258728	ENST00000556278.1	c.432+989A>G		intron_variant	Intron 4 of 7	5		ENSP00000451792.1

Frequencies

GnomAD3 genomes AF: 0.0749 AC: 11385 AN: 152036 Hom.: 589 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.0709

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0952

Gnomad OTH AF: 0.0793

GnomAD3 exomes AF: 0.0917 AC: 23055 AN: 251460 Hom.: 1330 AF XY: 0.0981 AC XY: 13331 AN XY: 135906

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.0640

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.00919

Gnomad SAS exome AF: 0.182

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.0933

Gnomad OTH exome AF: 0.0987

GnomAD4 exome AF: 0.0956 AC: 139784 AN: 1461832 Hom.: 7478 Cov.: 32 AF XY: 0.0986 AC XY: 71699 AN XY: 727220

Gnomad4 AFR exome AF: 0.0230

Gnomad4 AMR exome AF: 0.0656

Gnomad4 ASJ exome AF: 0.113

Gnomad4 EAS exome AF: 0.00673

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.0945

Gnomad4 OTH exome AF: 0.0966

GnomAD4 genome AF: 0.0748 AC: 11385 AN: 152154 Hom.: 589 Cov.: 32 AF XY: 0.0760 AC XY: 5656 AN XY: 74394

Gnomad4 AFR AF: 0.0239

Gnomad4 AMR AF: 0.0709

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.0952

Gnomad4 OTH AF: 0.0794

Alfa AF: 0.0896 Hom.: 1248

Bravo AF: 0.0654

TwinsUK AF: 0.101 AC: 373

ALSPAC AF: 0.0957 AC: 369

ESP6500AA AF: 0.0288 AC: 127

ESP6500EA AF: 0.0934 AC: 803

ExAC AF: 0.0920 AC: 11169

Asia WGS AF: 0.0760 AC: 263 AN: 3478

EpiCase AF: 0.0993

EpiControl AF: 0.0962

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Pathogenic:6 Uncertain:1 Benign:12 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:4 Benign:7 Other:1

Jun 10, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Sep 11, 2017

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2015

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Four variants in the GALT gene often occur together on the same chromosome (in cis) as part of a haplotype, which is referred to as the Duarte 2 variant: (c.378-27G>C, c.507+62G>A, c.508-24G>A, c.940A>G). Individuals that inherit the Duarte 2 variant from one parent and a more severe GALT variant from the other parent are affected with Duarte galactosemia, and typically have milder features of galactosemia (PMID: 25473725; 24718839; 19224951; 10424825). -

Jun 10, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Lifecell International Pvt. Ltd

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.940A>G (p.Asn314Asp) in the GALT gene has been reported previously in heterozygous and homozygous state in individuals affected with galactosemia. It is one of the most prevalent variants in the Indian population. This mutation effect may cause differences in the protein’s physiochemical characteristics that may be disturbed by either stabilizing or destabilizing the protein. Four variants in the GALT gene often occur together on the same chromosome (in cis) as part of a haplotype, which is referred to as the Duarte 2 variant: (c.378-27G>C, c.507+62G>A, c.508-24G>A, c.940A>G) (Kumar S et al., 2020; Klipstein et al., 2003; Lukac-Bajalo et al., 2002; Carney et al., 2009). This variant is reported with the allele frequency (9%) in the gnomAD Exomes. It is submitted to ClinVar with varying interpretations as Pathogenic/ Likely Pathogenic/ Benign/ Likely benign. The amino acid Asparagine at position 314 is changed to a Aspartic Acid changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster-Polymorphism) predict no damaging effect on protein structure and function for this variant. The amino acid change p.Asn314Asp in GALT is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -

Nov 10, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2 Uncertain:1 Benign:2 Other:1

Jun 24, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed on 25366/282804 (9%) alleles including multiple unrelated homozygous individuals in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 2011574, 25592817, 9222760, 27005423, 8892021, 19581158, 21228398, 11152465, 22963887, 25614870, 8198125, 15841485, 25087612, 16540753, 31028937, 31194252, 19224951) -

Nov 18, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GALT: BP4 -

Feb 13, 2018

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

GALT-related disorder Benign:1

Jun 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Galactosemia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GALT POLYMORPHISM (DUARTE, D2) Benign:1

May 01, 2009

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	18
DANN	Benign	0.77
DEOGEN2	Uncertain	0.53	.;D
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.61	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	-1.3	.;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.69	N;N
REVEL	Uncertain	0.38
Sift	Benign	1.0	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.0	.;B
Vest4		0.10
MPC		0.053
ClinPred		0.0012	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.61

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: rs2070074; hg19: chr9-34649442; COSMIC: COSV58840369; COSMIC: COSV58840369;