Genetic Variant ST3GAL5:c.82+1G>A (chr2-85888823-C-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_003896.4(ST3GAL5):c.82+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ST3GAL5
NM_003896.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.29

Publications

0 publications found

Variant links:

Genes affected

ST3GAL5 (HGNC:10872): (ST3 beta-galactoside alpha-2,3-sialyltransferase 5) Ganglioside GM3 is known to participate in the induction of cell differentiation, modulation of cell proliferation, maintenance of fibroblast morphology, signal transduction, and integrin-mediated cell adhesion. The protein encoded by this gene is a type II membrane protein which catalyzes the formation of GM3 using lactosylceramide as the substrate. The encoded protein is a member of glycosyltransferase family 29 and may be localized to the Golgi apparatus. Mutation in this gene has been associated with Amish infantile epilepsy syndrome. Transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ST3GAL5 Gene-Disease associations (from GenCC):

GM3 synthase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P

ST3GAL5 links:

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new If you want to explore the variant's impact on the transcript NM_003896.4, 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.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003896.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ST3GAL5	NM_003896.4	MANE Select	c.82+1G>A	splice_donor intron	N/A	NP_003887.3
ST3GAL5	NM_001354227.2		c.-190+1G>A	splice_donor intron	N/A	NP_001341156.1	A0A0S2Z4S6
ST3GAL5	NM_001354229.2		c.-134+1G>A	splice_donor intron	N/A	NP_001341158.1	A0A0S2Z4S6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ST3GAL5	ENST00000638572.2	TSL:1 MANE Select	c.82+1G>A	splice_donor intron	N/A	ENSP00000491316.1	Q9UNP4-1
ST3GAL5	ENST00000640418.1	TSL:5	c.139+4985G>A	intron	N/A	ENSP00000492098.1	A0A1W2PQR0
ST3GAL5	ENST00000639305.1	TSL:5	c.79+1G>A	splice_donor intron	N/A	ENSP00000492244.1	A0A1W2PRC6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1107228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

534708

African (AFR)

AF:

0.00

AC:

AN:

22236

American (AMR)

AF:

0.00

AC:

AN:

9952

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14278

East Asian (EAS)

AF:

0.00

AC:

AN:

23742

South Asian (SAS)

AF:

0.00

AC:

AN:

31742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22826

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2942

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

936090

Other (OTH)

AF:

0.00

AC:

AN:

43420

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Benign

0.31

PhyloP100

1.3

PromoterAI

-0.52

Under-expression

(source)

Mutation Taster

=16/84

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.90

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.90

Position offset: 1

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

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over