1-43824858-A-G

Variant names:

• chr1-43824858-A-G
• rs37458
• ENST00000372372.7:c.289A>G

Variant summary

Our verdict is Benign. The variant received -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. 14/17 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
• Publications: 33 publications found

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]

ST3GAL3 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 15

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• intellectual disability, autosomal recessive 12

  Inheritance: AR Classification: STRONG Submitted by: G2P
• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000284989 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 130378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ST3GAL3	NM_006279.5	c.209+9925A>G		intron_variant	Intron 4 of 11	ENST00000347631.8	NP_006270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ST3GAL3	ENST00000347631.8	c.209+9925A>G		intron_variant	Intron 4 of 11	5	NM_006279.5	ENSP00000317192.6
ENSG00000284989	ENST00000645057.1	n.*1531+9925A>G		intron_variant	Intron 18 of 25			ENSP00000494063.1

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

GnomAD2 exomes AF: 0.289 AC: 60821 AN: 210664 AF XY: 0.285

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 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

African (AFR) AF: 0.314 AC: 6555 AN: 20888

American (AMR) AF: 0.221 AC: 8756 AN: 39668

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 6923 AN: 21784

East Asian (EAS) AF: 0.149 AC: 5425 AN: 36320

South Asian (SAS) AF: 0.145 AC: 10466 AN: 72002

European-Finnish (FIN) AF: 0.363 AC: 18891 AN: 52044

Middle Eastern (MID) AF: 0.314 AC: 1419 AN: 4518

European-Non Finnish (NFE) AF: 0.348 AC: 179713 AN: 516314

Other (OTH) AF: 0.316 AC: 12214 AN: 38690

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

African (AFR) AF: 0.316 AC: 13090 AN: 41460

American (AMR) AF: 0.276 AC: 4213 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1104 AN: 3468

East Asian (EAS) AF: 0.141 AC: 729 AN: 5182

South Asian (SAS) AF: 0.139 AC: 670 AN: 4822

European-Finnish (FIN) AF: 0.351 AC: 3717 AN: 10584

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23601 AN: 67996

Other (OTH) AF: 0.339 AC: 717 AN: 2112

Alfa AF: 0.337 Hom.: 37682

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 15 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
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
PhyloP100		-0.15
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs37458; hg19: chr1-44290530; COSMIC: COSV53510755;