chr1-43736285-G-A

Variant names:

• chr1-43736285-G-A
• rs900948973
• NM_006279.5:c.23G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006279.5(ST3GAL3):​c.23G>A​(p.Arg8His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ST3GAL3 NM_006279.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.71
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intellectual disability, autosomal recessive 12

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006279.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ST3GAL3	NM_006279.5	MANE Select	c.23G>A	p.Arg8His	missense	Exon 2 of 12	NP_006270.1	Q11203-1
	ST3GAL3	NM_001350619.2		c.23G>A	p.Arg8His	missense	Exon 2 of 13	NP_001337548.1	A0A2R8YDJ6
	ST3GAL3	NM_174963.5		c.23G>A	p.Arg8His	missense	Exon 2 of 13	NP_777623.2	Q11203-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ST3GAL3	ENST00000347631.8	TSL:5 MANE Select	c.23G>A	p.Arg8His	missense	Exon 2 of 12	ENSP00000317192.6	Q11203-1
	ST3GAL3	ENST00000372372.7	TSL:1	c.23G>A	p.Arg8His	missense	Exon 2 of 12	ENSP00000361447.2	Q11203-19
	ST3GAL3	ENST00000361746.9	TSL:1	c.23G>A	p.Arg8His	missense	Exon 2 of 13	ENSP00000354657.5	A0A2U3TZK9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.030	D
MutationAssessor	Benign	0.97	L
PhyloP100		6.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.41
Sift	Benign	0.17	T
Sift4G	Benign	0.36	T
Polyphen		1.0	D
Vest4		0.67
MutPred		0.74		Loss of helix (P = 0.0558)
MVP		0.92
MPC		0.71
ClinPred		0.84	D
GERP RS		5.9
PromoterAI		-0.032	Neutral
Varity_R		0.10
gMVP		0.57
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs900948973; hg19: chr1-44201956; COSMIC: COSV99496061; COSMIC: COSV99496061;