rs559756386

chr2-85888869-G-Achr2-85888869-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003896.4(ST3GAL5):c.37C>T(p.Pro13Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 1,366,398 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P13T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (30 hom.)
• Consequence: ST3GAL5 NM_003896.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.114

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004235208).
• BP6: Variant 2-85888869-G-A is Benign according to our data. Variant chr2-85888869-G-A is described in ClinVar as [Benign]. Clinvar id is 193261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00377 (571/151588) while in subpopulation SAS AF= 0.00849 (41/4828). AF 95% confidence interval is 0.00643. There are 1 homozygotes in gnomad4. There are 256 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ST3GAL5	NM_003896.4	c.37C>T	p.Pro13Ser	missense_variant	1/7	ENST00000638572.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ST3GAL5	ENST00000638572.2	c.37C>T	p.Pro13Ser	missense_variant	1/7	1	NM_003896.4	A1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 569 AN: 151480 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000991

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00487

Gnomad ASJ AF: 0.00318

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00584

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00568 AC: 381 AN: 67032 Hom.: 3 AF XY: 0.00679 AC XY: 264 AN XY: 38880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00331

Gnomad ASJ exome AF: 0.00263

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00481

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00591 AC: 7183 AN: 1214810 Hom.: 30 Cov.: 30 AF XY: 0.00625 AC XY: 3731 AN XY: 596516

Gnomad4 AFR exome AF: 0.000481

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.00273

Gnomad4 EAS exome AF: 0.0000405

Gnomad4 SAS exome AF: 0.0128

Gnomad4 FIN exome AF: 0.000278

Gnomad4 NFE exome AF: 0.00606

Gnomad4 OTH exome AF: 0.00593

GnomAD4 genome AF: 0.00377 AC: 571 AN: 151588 Hom.: 1 Cov.: 33 AF XY: 0.00346 AC XY: 256 AN XY: 74056

Gnomad4 AFR AF: 0.000988

Gnomad4 AMR AF: 0.00487

Gnomad4 ASJ AF: 0.00318

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00586

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00357

ExAC AF: 0.00934 AC: 116

Asia WGS AF: 0.00372 AC: 12 AN: 3238

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GM3 synthase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ST3GAL5: BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.68	T;T;T
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.76	T
Polyphen		0.0030	B;.;.
Vest4		0.15
MVP		0.099
MPC		0.31
ClinPred		0.018	T
GERP RS		1.2
Varity_R		0.13
gMVP		0.25

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

Other links and lift over

dbSNP: rs559756386; hg19: chr2-86115992;