Genetic Variant GAL3ST1:p.Asn66Lys (chr22-30556027-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001318104.2(GAL3ST1):c.198C>A(p.Asn66Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GAL3ST1
NM_001318104.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.306

Publications

1 publications found

Variant links:

Genes affected

GAL3ST1 (HGNC:24240): (galactose-3-O-sulfotransferase 1) Sulfonation, an important step in the metabolism of many drugs, xenobiotics, hormones, and neurotransmitters, is catalyzed by sulfotransferases. This gene encodes galactosylceramide sulfotransferase, which catalyzes the sulfation of membrane glycolipids including the final step in the synthesis of sulfatide, a major lipid component of the myelin sheath. This gene exhibits elevated expression in ovarian epithelial carcinoma and the encoded enzyme exhibits elevated activity in renal cell carcinoma. Mutations in this gene may be associated with reduced insulin resistance. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

GAL3ST1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity G3ST1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2421512).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318104.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAL3ST1	NM_001318104.2	MANE Select	c.198C>A	p.Asn66Lys	missense	Exon 4 of 4	NP_001305033.1	Q99999
GAL3ST1	NM_001318107.2		c.201C>A	p.Asn67Lys	missense	Exon 4 of 4	NP_001305036.1
GAL3ST1	NM_001318114.2		c.201C>A	p.Asn67Lys	missense	Exon 3 of 3	NP_001305043.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAL3ST1	ENST00000406361.6	TSL:2 MANE Select	c.198C>A	p.Asn66Lys	missense	Exon 4 of 4	ENSP00000385207.1	Q99999
GAL3ST1	ENST00000338911.6	TSL:1	c.198C>A	p.Asn66Lys	missense	Exon 2 of 2	ENSP00000343234.5	Q99999
GAL3ST1	ENST00000401975.5	TSL:1	c.198C>A	p.Asn66Lys	missense	Exon 4 of 4	ENSP00000384388.1	Q99999

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000807

AC:

AN:

247898

AF XY:

0.00000743

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:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460484

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726582

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111888

Other (OTH)

AF:

0.0000166

AC:

AN:

60380

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

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000825

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.13

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.044

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.99

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.78

M_CAP

Benign

0.031

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PhyloP100

0.31

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.35

REVEL

Benign

0.079

Sift

Benign

0.79

Sift4G

Benign

0.21

Polyphen

0.046

Vest4

0.14

MutPred

0.60

Gain of ubiquitination at N66 (P = 0.0031)

MVP

0.51

MPC

1.3

ClinPred

0.032

GERP RS

-2.3

Varity_R

0.049

gMVP

0.73

Mutation Taster

=89/11

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over