rs2070074

Positions:

chr9-34649445-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBA1

The ENST00000378842.8(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). Synonymous variant affecting the same amino acid position (i.e. N314N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.075 ( 589 hom., cov: 32)

Exomes 𝑓: 0.096 ( 7478 hom. )

Consequence

GALT
ENST00000378842.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:6U:1B:12O:2

Conservation

PhyloP100: 1.74

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in ENST00000378842.8

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/exons	MANE	Protein	UniProt
GALT	NM_000155.4 linkuse as main transcript	c.940A>G	p.Asn314Asp	missense_variant	10/11	ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2 linkuse as main transcript	c.613A>G	p.Asn205Asp	missense_variant	8/9		NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8 linkuse as main transcript	c.940A>G	p.Asn314Asp	missense_variant	10/11	1	NM_000155.4	ENSP00000368119	P1	P07902-1

Frequencies

GnomAD3 genomes

AF:

0.0749

AC:

11385

AN:

152036

Hom.:

589

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0986

AC XY:

71699

AN XY:

727220

show subpopulations

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.:

AF XY:

0.0760

AC XY:

5656

AN XY:

74394

show subpopulations

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:6Uncertain:1Benign:12Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Pathogenic:4Benign:7Other:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Lifecell International Pvt. Ltd	-	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 10, 2023	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jun 10, 2016	- -

not provided

Pathogenic:2Uncertain:1Benign:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 18, 2014	- -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2018	- 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	GeneDx	Jul 15, 2021	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) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	GALT: BP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 24, 2022	- -

GALT-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

GALT POLYMORPHISM (DUARTE, D2)

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

May 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Uncertain

0.53

.;D

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.61

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

-1.3

.;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.49

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over