chr9-34647529-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000155.4(GALT):c.290A>G(p.Asn97Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N97D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GALT
NM_000155.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 8.36

Publications

6 publications found

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 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

GALT links:

ENSG00000258728 (HGNC:):

ENSG00000258728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000155.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-34647528-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 593326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 104 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 0.91493 (below the threshold of 3.09). Trascript score misZ: 1.8645 (below the threshold of 3.09). GenCC associations: The gene is linked to galactosemia, classic galactosemia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 9-34647529-A-G is Pathogenic according to our data. Variant chr9-34647529-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALT	NM_000155.4 link	c.290A>G	p.Asn97Ser	missense_variant	Exon 3 of 11	ENST00000378842.8	NP_000146.2	P07902-1B2RAT6A0A0S2Z3Y7
GALT	NM_001258332.2 link	c.50+271A>G		intron_variant	Intron 2 of 8		NP_001245261.1	P07902-2B2RAT6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8 link	c.290A>G	p.Asn97Ser	missense_variant	Exon 3 of 11	1	NM_000155.4	ENSP00000368119.4		P07902-1
ENSG00000258728	ENST00000556278.1 link	c.252+271A>G		intron_variant	Intron 2 of 7	5		ENSP00000451792.1		G3V4G9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251494

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000198

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Pathogenic:4

Jul 22, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 06, 2019

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GALT c.290A>G (p.Asn97Ser, legacy name c.318A>G) results in a conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain (IPR005849) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Five predict the variant creates a cryptic 3 acceptor site. A functional study, Ashino_1995 found the variant supports these predictions. The variant allele was found at a frequency of 4e-06 in 251494 control chromosomes (gnomAD). c.290A>G has been reported in the literature in individuals affected with Galactosemia (eg. Ashino_1995, Shin_2004, Waisbren_2012). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (eg. Ashino_1995). A ClinVar submission (evaluation after 2014) cites the variant as likely pathogenic. Furthermore, another variant affecting the same codon, N97D, and nearby codons, F95L, D98N, D98H, have been reported in association with Galactosaemia (via HGMD). Therefore, suggesting this region is important for GALT protein function. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 28, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 97 of the GALT protein (p.Asn97Ser). This variant is present in population databases (rs111033669, gnomAD 0.0009%). This missense change has been observed in individual(s) with classic galactosemia (PMID: 7550229, 15633893). This variant is also known as 318A>G. ClinVar contains an entry for this variant (Variation ID: 25146). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALT protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Asn97 amino acid residue in GALT. Other variant(s) that disrupt this residue have been observed in individuals with GALT-related conditions (PMID: 22944367), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

GALT-related disorder

Pathogenic:1

May 10, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The GALT c.290A>G variant is predicted to result in the amino acid substitution p.Asn97Ser. This variant, also referred to as c.318A>G using legacy nomenclature, has been reported in the homozygous and compound heterozygous states in multiple individuals with galactosemia (see for example, Table 1, Ashino et al. 1995. PubMed ID: 7550229; Table 3, Shin and Podskarbi. 2004. PubMed ID: 15633893; Table 2, Waisbren et al. 2011. PubMed ID: 21779791). An RT-PCR study suggests this variant impacts mRNA splicing via using of a cryptic splice acceptor site and leads to a frameshift loss-of-function effect (Figure 2, Ashino et al. 1995. PubMed ID: 7550229). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Jan 17, 2013

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.9

PhyloP100

8.4

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.94

MutPred

0.94

Gain of glycosylation at N97 (P = 0.0155);

MVP

0.99

MPC

1.7

ClinPred

1.0

GERP RS

5.5

Varity_R

0.94

gMVP

0.99

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.30

Position offset: 1

DS_AL_spliceai

0.24

Position offset: -37

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over