rs12140044

Variant names:

• chr1-43899619-C-T
• rs12140044
• NM_006279.5:c.636C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006279.5(ST3GAL3):​c.636C>T​(p.Gly212Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00565 in 1,614,132 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (38 hom.)
• Consequence: ST3GAL3 NM_006279.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0760
• Publications: 3 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.139).
• BP6: Variant 1-43899619-C-T is Benign according to our data. Variant chr1-43899619-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.076 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00427 (650/152312) while in subpopulation NFE AF = 0.00651 (443/68024). AF 95% confidence interval is 0.00601. There are 4 homozygotes in GnomAd4. There are 311 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.636C>T	p.Gly212Gly	synonymous	Exon 9 of 12	NP_006270.1	Q11203-1
	ST3GAL3	NM_001350619.2		c.681C>T	p.Gly227Gly	synonymous	Exon 9 of 13	NP_001337548.1	A0A2R8YDJ6
	ST3GAL3	NM_174963.5		c.843C>T	p.Gly281Gly	synonymous	Exon 10 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.636C>T	p.Gly212Gly	synonymous	Exon 9 of 12	ENSP00000317192.6	Q11203-1
	ST3GAL3	ENST00000372372.7	TSL:1	c.750C>T	p.Gly250Gly	synonymous	Exon 9 of 12	ENSP00000361447.2	Q11203-19
	ST3GAL3	ENST00000361746.9	TSL:1	c.729C>T	p.Gly243Gly	synonymous	Exon 10 of 13	ENSP00000354657.5	A0A2U3TZK9

Frequencies

GnomAD3 genomes AF: 0.00427 AC: 650 AN: 152194 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00980

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00651

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00450 AC: 1130 AN: 251368 AF XY: 0.00438

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.00691

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00579 AC: 8462 AN: 1461820 Hom.: 38 Cov.: 31 AF XY: 0.00562 AC XY: 4084 AN XY: 727208

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.00134 AC: 60 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00980 AC: 523 AN: 53354

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00681 AC: 7570 AN: 1112006

Other (OTH) AF: 0.00440 AC: 266 AN: 60394

GnomAD4 genome AF: 0.00427 AC: 650 AN: 152312 Hom.: 4 Cov.: 32 AF XY: 0.00418 AC XY: 311 AN XY: 74472

African (AFR) AF: 0.00144 AC: 60 AN: 41582

American (AMR) AF: 0.00242 AC: 37 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00980 AC: 104 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00651 AC: 443 AN: 68024

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00515 Hom.: 2

Bravo AF: 0.00354

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00556

EpiControl AF: 0.00634

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		-0.076
PromoterAI		-0.064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12140044; hg19: chr1-44365291;