chr2-85888869-G-T

Variant names:

• chr2-85888869-G-T
• rs559756386
• NM_003896.4:c.37C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003896.4(ST3GAL5):​c.37C>A​(p.Pro13Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,214,820 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P13S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ST3GAL5 NM_003896.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.114
• Publications: 2 publications found

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: ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13401899).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ST3GAL5	NM_003896.4	c.37C>A	p.Pro13Thr	missense_variant	Exon 1 of 7	ENST00000638572.2	NP_003887.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ST3GAL5	ENST00000638572.2	c.37C>A	p.Pro13Thr	missense_variant	Exon 1 of 7	1	NM_003896.4	ENSP00000491316.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000149 AC: 1 AN: 67032 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.000511

GnomAD4 exome AF: 0.00000412 AC: 5 AN: 1214820 Hom.: 0 Cov.: 30 AF XY: 0.00000335 AC XY: 2 AN XY: 596522

African (AFR) AF: 0.00 AC: 0 AN: 24926

American (AMR) AF: 0.0000896 AC: 2 AN: 22320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19792

East Asian (EAS) AF: 0.00 AC: 0 AN: 24712

South Asian (SAS) AF: 0.00 AC: 0 AN: 58092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3344

European-Non Finnish (NFE) AF: 0.00000305 AC: 3 AN: 984682

Other (OTH) AF: 0.00 AC: 0 AN: 48214

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

GM3 synthase deficiency Uncertain:1

May 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 13 of the ST3GAL5 protein (p.Pro13Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ST3GAL5-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.
PhyloP100		0.11
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.0	.;N;.
REVEL	Benign	0.051
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		0.079	B;.;.
Vest4		0.19
MutPred		0.17		Gain of phosphorylation at P13 (P = 0.0034);Gain of phosphorylation at P13 (P = 0.0034);Gain of phosphorylation at P13 (P = 0.0034);
MVP		0.14
MPC		0.34
ClinPred		0.12	T
GERP RS		1.2
PromoterAI		0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.26
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs559756386; hg19: chr2-86115992;