chr2-85840154-C-T

Variant names:

• chr2-85840154-C-T
• rs200683924
• NM_003896.4:c.1247G>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.1247G>A​(p.Arg416His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,878 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. R416L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ST3GAL5 NM_003896.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.49
• Publications: 6 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P

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=0.21406114).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ST3GAL5	NM_003896.4	MANE Select	c.1247G>A	p.Arg416His	missense	Exon 7 of 7	NP_003887.3
	ST3GAL5	NM_001042437.2		c.1178G>A	p.Arg393His	missense	Exon 7 of 7	NP_001035902.1	Q9UNP4-3
	ST3GAL5	NM_001354227.2		c.1163G>A	p.Arg388His	missense	Exon 8 of 8	NP_001341156.1	A0A0S2Z4S6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ST3GAL5	ENST00000638572.2	TSL:1 MANE Select	c.1247G>A	p.Arg416His	missense	Exon 7 of 7	ENSP00000491316.1	Q9UNP4-1
	ST3GAL5	ENST00000393808.8	TSL:1	c.1178G>A	p.Arg393His	missense	Exon 7 of 7	ENSP00000377397.3	Q9UNP4-3
	ST3GAL5	ENST00000393805.6	TSL:1	c.1163G>A	p.Arg388His	missense	Exon 7 of 7	ENSP00000377394.1	Q9UNP4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251388 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727238

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000362 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	GM3 synthase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		7.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.084	T
Polyphen		0.70	P
Vest4		0.13
MutPred		0.26		Loss of solvent accessibility (P = 0.0128)
MVP		0.40
MPC		0.53
ClinPred		0.58	D
GERP RS		5.8
Varity_R		0.070
gMVP		0.37
Mutation Taster		=79/21	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: rs200683924; hg19: chr2-86067277; COSMIC: COSV66150653; COSMIC: COSV66150653;