1-43736380-A-G

Position:

• chr1-43736380-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006279.5(ST3GAL3):​c.118A>G​(p.Asn40Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ST3GAL3 NM_006279.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05

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]

ENSG00000284989 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1168026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ST3GAL3	NM_006279.5	c.118A>G	p.Asn40Asp	missense_variant, splice_region_variant	2/12	ENST00000347631.8	NP_006270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ST3GAL3	ENST00000347631.8	c.118A>G	p.Asn40Asp	missense_variant, splice_region_variant	2/12	5	NM_006279.5	ENSP00000317192.6
ENSG00000284989	ENST00000645057.1	n.*1440A>G		splice_region_variant, non_coding_transcript_exon_variant	16/26			ENSP00000494063.1
ENSG00000284989	ENST00000645057.1	n.*1440A>G		3_prime_UTR_variant	16/26			ENSP00000494063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2019

The c.118A>G variant (also known as p.N40D), located in coding exon 1 of the ST3GAL3 gene, results from an A to G substitution at nucleotide position 118. The amino acid change results in asparagine to aspartic acid at codon 40, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.97
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.61	T;T;T;T;T;T;T;T;T;.;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
PROVEAN	Benign	0.29	N;N;.;.;.;.;.;N;N;N;N
REVEL	Benign	0.046
Sift	Benign	0.87	T;T;.;.;.;.;.;T;T;T;T
Sift4G	Benign	0.97	T;T;T;.;.;.;.;T;T;T;T
Polyphen		0.0	B;B;B;.;B;.;.;B;B;B;B
Vest4		0.37
MutPred		0.29		Loss of ubiquitination at K40 (P = 0.0107);Loss of ubiquitination at K40 (P = 0.0107);Loss of ubiquitination at K40 (P = 0.0107);Loss of ubiquitination at K40 (P = 0.0107);Loss of ubiquitination at K40 (P = 0.0107);Loss of ubiquitination at K40 (P = 0.0107);Loss of ubiquitination at K40 (P = 0.0107);Loss of ubiquitination at K40 (P = 0.0107);Loss of ubiquitination at K40 (P = 0.0107);Loss of ubiquitination at K40 (P = 0.0107);Loss of ubiquitination at K40 (P = 0.0107);
MVP		0.093
ClinPred		0.30	T
GERP RS		3.7

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: rs572942778; hg19: chr1-44202051;