2-85847922-C-G

Variant names:

• chr2-85847922-C-G
• NM_003896.4:c.601G>C
• ST3GAL5 p.Gly201Arg

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS1 PM1 PM2 PP3_Strong

The NM_003896.4(ST3GAL5):​c.601G>C​(p.Gly201Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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 Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ST3GAL5 NM_003896.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.16
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PS1: Transcript NM_003896.4 (ST3GAL5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_003896.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

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.601G>C	p.Gly201Arg	missense	Exon 4 of 7	NP_003887.3
	ST3GAL5	NM_001042437.2		c.532G>C	p.Gly178Arg	missense	Exon 4 of 7	NP_001035902.1	Q9UNP4-3
	ST3GAL5	NM_001354227.2		c.517G>C	p.Gly173Arg	missense	Exon 5 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.601G>C	p.Gly201Arg	missense	Exon 4 of 7	ENSP00000491316.1	Q9UNP4-1
	ST3GAL5	ENST00000393808.8	TSL:1	c.532G>C	p.Gly178Arg	missense	Exon 4 of 7	ENSP00000377397.3	Q9UNP4-3
	ST3GAL5	ENST00000393805.6	TSL:1	c.517G>C	p.Gly173Arg	missense	Exon 4 of 7	ENSP00000377394.1	Q9UNP4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.82
gMVP		0.97
Mutation Taster		=1/99	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-86075045;