Genetic Variant ST8SIA3:p.Phe248Leu (chr18-57357352-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015879.3(ST8SIA3):c.742T>C(p.Phe248Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000979 in 1,613,346 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

ST8SIA3
NM_015879.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.65

Variant links:

Genes affected

ST8SIA3 (HGNC:14269): (ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 3) Enables alpha-N-acetylneuraminate alpha-2,8-sialyltransferase activity and identical protein binding activity. Involved in several processes, including ganglioside biosynthetic process; glycoprotein metabolic process; and protein sialylation. Predicted to be located in Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

ST8SIA3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ST8SIA3	NM_015879.3 link	c.742T>C	p.Phe248Leu	missense_variant	Exon 3 of 4	ENST00000324000.4	NP_056963.2	O43173Q59GW3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ST8SIA3	ENST00000324000.4 link	c.742T>C	p.Phe248Leu	missense_variant	Exon 3 of 4	1	NM_015879.3	ENSP00000320431.2		O43173
ST8SIA3	ENST00000586360.1 link	c.199T>C	p.Phe67Leu	missense_variant	Exon 1 of 3	3		ENSP00000467752.1		K7EQB3

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000157

AC:

AN:

248944

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

135066

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000357

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.0000951

AC:

139

AN:

1461134

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

726850

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000379

Gnomad4 NFE exome

AF:

0.0000773

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000125

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.000159

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.742T>C (p.F248L) alteration is located in exon 3 (coding exon 3) of the ST8SIA3 gene. This alteration results from a T to C substitution at nucleotide position 742, causing the phenylalanine (F) at amino acid position 248 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.57

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.31

Sift

Benign

0.053

Sift4G

Benign

0.077

Polyphen

0.91

Vest4

0.89

MutPred

0.65

Loss of catalytic residue at P246 (P = 0.1366);

MVP

0.17

MPC

1.1

ClinPred

0.14

GERP RS

5.8

Varity_R

0.76

gMVP

0.89

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over