rs745451424

Variant names:

• chr1-43898238-A-G
• rs745451424
• NM_006279.5:c.401A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001350619.2(ST3GAL3):​c.446A>G​(p.Asn149Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N149Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ST3GAL3 NM_001350619.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 5.27
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350619.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ST3GAL3	NM_006279.5	MANE Select	c.401A>G	p.Asn134Ser	missense	Exon 7 of 12	NP_006270.1
	ST3GAL3	NM_001350619.2		c.446A>G	p.Asn149Ser	missense	Exon 7 of 13	NP_001337548.1
	ST3GAL3	NM_174963.5		c.608A>G	p.Asn203Ser	missense	Exon 8 of 13	NP_777623.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ST3GAL3	ENST00000347631.8	TSL:5 MANE Select	c.401A>G	p.Asn134Ser	missense	Exon 7 of 12	ENSP00000317192.6
	ST3GAL3	ENST00000372372.7	TSL:1	c.515A>G	p.Asn172Ser	missense	Exon 7 of 12	ENSP00000361447.2
	ST3GAL3	ENST00000361746.9	TSL:1	c.494A>G	p.Asn165Ser	missense	Exon 8 of 13	ENSP00000354657.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251252 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461610 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727110

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy (1)
-	1	-	Epilepsy due to perinatal stroke (1)
-	-	1	Intellectual disability, autosomal recessive 12;C3554316:Developmental and epileptic encephalopathy, 15 (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.62
CADD	Uncertain	26
DANN	Benign	0.86
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.28	N
PhyloP100		5.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.12
Sift	Benign	0.46	T
Sift4G	Benign	0.48	T
Polyphen		0.18	B
Vest4		0.44
MutPred		0.36		Loss of helix (P = 0.079)
MVP		0.093
MPC		0.74
ClinPred		0.15	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.39
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745451424; hg19: chr1-44363910;