rs2070074

Variant names:

Variant summary

Our verdict is The variant received -8 classification points (ACMG Germline Pathogenicity v2019). 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 cumulative frequency of 0.0937 (AC=151,169) in the gnomAD database across 1,613,986 control chromosomes, including 8,067 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.178. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.N314= (synonymous): Likely_benign (ClinVar VariationId 1549436, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.075 ( 589 hom., cov: 32)

Exomes 𝑓: 0.096 ( 7478 hom. )

Consequence

GALT
NM_000155.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:8U:3B:11O:2

Conservation

PhyloP100: 1.74

Publications

175 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: G2P, Natera, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet
galactosemia
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women's Health

GALT links:

ENSG00000258728 (HGNC:):

ENSG00000258728 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000155.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -8 points.

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1777 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000155.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALT	NM_000155.4	MANE Select	c.940A>G	p.Asn314Asp	missense	Exon 10 of 11	NP_000146.2
	GALT	NM_001258332.2		c.613A>G	p.Asn205Asp	missense	Exon 8 of 9	NP_001245261.1	P07902-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GALT	ENST00000378842.8	TSL:1 MANE Select	c.940A>G	p.Asn314Asp	missense	Exon 10 of 11	ENSP00000368119.4	P07902-1
ENSG00000258728	ENST00000556278.1	TSL:5	c.432+989A>G		intron	N/A	ENSP00000451792.1	G3V4G9
GALT	ENST00000902340.1		c.979A>G	p.Asn327Asp	missense	Exon 9 of 10	ENSP00000572399.1

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

GnomAD2 exomes

AF:

0.0917

AC:

23055

AN:

251460

AF XY:

0.0981

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 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

African (AFR)

AF:

0.0230

AC:

771

AN:

33480

American (AMR)

AF:

0.0656

AC:

2935

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.113

AC:

2965

AN:

26136

East Asian (EAS)

AF:

0.00673

AC:

267

AN:

39700

South Asian (SAS)

AF:

0.180

AC:

15532

AN:

86256

European-Finnish (FIN)

AF:

0.108

AC:

5749

AN:

53402

Middle Eastern (MID)

AF:

0.113

AC:

652

AN:

5768

European-Non Finnish (NFE)

AF:

0.0945

AC:

105076

AN:

1111974

Other (OTH)

AF:

0.0966

AC:

5837

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

7324

14649

21973

29298

36622

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3858

7716

11574

15432

19290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0748

AC:

11385

AN:

152154

Hom.:

589

Cov.:

AF XY:

0.0760

AC XY:

5656

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0239

AC:

994

AN:

41514

American (AMR)

AF:

0.0709

AC:

1083

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.109

AC:

376

AN:

3462

East Asian (EAS)

AF:

0.0108

AC:

AN:

5170

South Asian (SAS)

AF:

0.173

AC:

834

AN:

4816

European-Finnish (FIN)

AF:

0.110

AC:

1168

AN:

10604

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0952

AC:

6475

AN:

67984

Other (OTH)

AF:

0.0794

AC:

168

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

524

1048

1573

2097

2621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0858

Hom.:

2230

Bravo

AF:

0.0654

Asia WGS

AF:

0.0760

AC:

263

AN:

3478

EpiCase

AF:

0.0993

EpiControl

AF:

0.0962

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.00376

AC:

461

AN:

122470

Turkish Variome

AF:

0.136

AC:

917

AN:

6722

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.0117

AC:

105

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.0670

AC:

157

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity; other

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase (13)

not provided (7)

GALT-related disorder (2)

GALT POLYMORPHISM (DUARTE, D2) (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.34

MutationAssessor

Benign

-1.3

PhyloP100

1.7

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.69

REVEL

Uncertain

0.38

Sift

Benign

1.0

Sift4G

Benign

0.70

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.61

Mutation Taster

=88/12

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over