rs37458

Positions:

• chr1-43824858-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000372372.7(ST3GAL3):​c.289A>G​(p.Thr97Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 954,350 control chromosomes in the GnomAD database, including 50,063 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7883 hom., cov: 32)
  • Exomes 𝑓: 0.31 (42180 hom.)
• Consequence: ST3GAL3 ENST00000372372.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.146

Genes affected

ST3GAL3 (HGNC:10866): (ST3 beta-galactoside alpha-2,3-sialyltransferase 3) The protein encoded by this gene is a type II membrane protein that catalyzes the transfer of sialic acid from CMP-sialic acid to galactose-containing substrates. The encoded protein is normally found in the Golgi apparatus but can be proteolytically processed to a soluble form. This protein is a member of glycosyltransferase family 29. Mutations in this gene have been associated with a form of autosomal recessive nonsymdromic cognitive disability as well as infantile epileptic encephalopathy. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019977093).
• BP6: Variant 1-43824858-A-G is Benign according to our data. Variant chr1-43824858-A-G is described in ClinVar as [Benign]. Clinvar id is 130378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43824858-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ST3GAL3	NM_006279.5	c.209+9925A>G		intron_variant		ENST00000347631.8	NP_006270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ST3GAL3	ENST00000347631.8	c.209+9925A>G		intron_variant		5	NM_006279.5	ENSP00000317192	A1

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48312 AN: 152004 Hom.: 7879 Cov.: 32

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.338

GnomAD3 exomes AF: 0.289 AC: 60821 AN: 210664 Hom.: 9505 AF XY: 0.285 AC XY: 32269 AN XY: 113366

Gnomad AFR exome AF: 0.323

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.316

Gnomad EAS exome AF: 0.136

Gnomad SAS exome AF: 0.144

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.357

Gnomad OTH exome AF: 0.316

GnomAD4 exome AF: 0.312 AC: 250362 AN: 802228 Hom.: 42180 Cov.: 11 AF XY: 0.306 AC XY: 129416 AN XY: 422890

Gnomad4 AFR exome AF: 0.314

Gnomad4 AMR exome AF: 0.221

Gnomad4 ASJ exome AF: 0.318

Gnomad4 EAS exome AF: 0.149

Gnomad4 SAS exome AF: 0.145

Gnomad4 FIN exome AF: 0.363

Gnomad4 NFE exome AF: 0.348

Gnomad4 OTH exome AF: 0.316

GnomAD4 genome AF: 0.318 AC: 48328 AN: 152122 Hom.: 7883 Cov.: 32 AF XY: 0.312 AC XY: 23179 AN XY: 74382

Gnomad4 AFR AF: 0.316

Gnomad4 AMR AF: 0.276

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.139

Gnomad4 FIN AF: 0.351

Gnomad4 NFE AF: 0.347

Gnomad4 OTH AF: 0.339

Alfa AF: 0.338 Hom.: 18173

Bravo AF: 0.316

TwinsUK AF: 0.351 AC: 1301

ALSPAC AF: 0.357 AC: 1377

ESP6500AA AF: 0.309 AC: 1361

ESP6500EA AF: 0.349 AC: 2985

ExAC AF: 0.271 AC: 32013

Asia WGS AF: 0.159 AC: 557 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Intellectual disability, autosomal recessive 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Developmental and epileptic encephalopathy, 15 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.3
DANN	Benign	0.30
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00020	N
LIST_S2	Benign	0.34	T;T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P
PROVEAN	Benign	-0.17	N;.;.;N;N
REVEL	Benign	0.0050
Sift	Benign	0.73	T;.;.;T;T
Sift4G	Benign	0.25	T;.;.;T;T
Polyphen		0.0	B;.;B;B;.
Vest4		0.022
MPC		0.56
ClinPred		0.0015	T
GERP RS		-0.028

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs37458; hg19: chr1-44290530; COSMIC: COSV53510755;