Genetic Variant GALT:p.Leu218Leu (chr9-34648421-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000155.4(GALT):c.652C>T(p.Leu218Leu) 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

Scores

Clinical Significance

Benign; other criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 0.837

Publications

37 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, Orphanet, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -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 VariationId is 39372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALT	NM_000155.4	MANE Select	c.652C>T	p.Leu218Leu	synonymous	Exon 7 of 11	NP_000146.2
	GALT	NM_001258332.2		c.325C>T	p.Leu109Leu	synonymous	Exon 5 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.652C>T	p.Leu218Leu	synonymous	Exon 7 of 11	ENSP00000368119.4	P07902-1
ENSG00000258728	ENST00000556278.1	TSL:5	c.397C>T	p.Leu133Leu	synonymous	Exon 4 of 8	ENSP00000451792.1	G3V4G9
GALT	ENST00000902340.1		c.691C>T	p.Leu231Leu	synonymous	Exon 6 of 10	ENSP00000572399.1

Frequencies

GnomAD3 genomes

AF:

0.0279

AC:

4250

AN:

152144

Hom.:

100

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0373

AC:

9391

AN:

251466

AF XY:

0.0415

show subpopulations

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 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.:

AF XY:

0.0367

AC XY:

26696

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0127

AC:

426

AN:

33480

American (AMR)

AF:

0.0175

AC:

783

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0623

AC:

1627

AN:

26136

East Asian (EAS)

AF:

0.000277

AC:

AN:

39700

South Asian (SAS)

AF:

0.104

AC:

9012

AN:

86258

European-Finnish (FIN)

AF:

0.0398

AC:

2124

AN:

53412

Middle Eastern (MID)

AF:

0.0664

AC:

383

AN:

5766

European-Non Finnish (NFE)

AF:

0.0301

AC:

33451

AN:

1111992

Other (OTH)

AF:

0.0384

AC:

2322

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

3361

6723

10084

13446

16807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1296

2592

3888

5184

6480

<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:

0.0279

AC:

4248

AN:

152262

Hom.:

Cov.:

AF XY:

0.0292

AC XY:

2177

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0118

AC:

491

AN:

41552

American (AMR)

AF:

0.0222

AC:

339

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0597

AC:

207

AN:

3466

East Asian (EAS)

AF:

0.00155

AC:

AN:

5172

South Asian (SAS)

AF:

0.103

AC:

498

AN:

4824

European-Finnish (FIN)

AF:

0.0425

AC:

451

AN:

10618

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0310

AC:

2109

AN:

68016

Other (OTH)

AF:

0.0350

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

211

422

633

844

1055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0292

Hom.:

208

Bravo

AF:

0.0233

Asia WGS

AF:

0.0420

AC:

145

AN:

3478

EpiCase

AF:

0.0382

EpiControl

AF:

0.0356

ClinVar

ClinVar submissions

Significance:Benign; other

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase (7)

not provided (4)

not specified (2)

Galactosemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.0

(source)

DANN

Benign

0.82

PhyloP100

0.84

Mutation Taster

=100/0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over