chr2-85840003-AT-A

Variant names:

• chr2-85840003-AT-A
• rs550737011
• NM_003896.4:c.*140delA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_003896.4(ST3GAL5):​c.*140delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,341,330 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (7 hom.)
• Consequence: ST3GAL5 NM_003896.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0400
• Publications: 0 publications found

Genes affected

ST3GAL5 (HGNC:10872): (ST3 beta-galactoside alpha-2,3-sialyltransferase 5) Ganglioside GM3 is known to participate in the induction of cell differentiation, modulation of cell proliferation, maintenance of fibroblast morphology, signal transduction, and integrin-mediated cell adhesion. The protein encoded by this gene is a type II membrane protein which catalyzes the formation of GM3 using lactosylceramide as the substrate. The encoded protein is a member of glycosyltransferase family 29 and may be localized to the Golgi apparatus. Mutation in this gene has been associated with Amish infantile epilepsy syndrome. Transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ST3GAL5 Gene-Disease associations (from GenCC):

• GM3 synthase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00186 (283/152182) while in subpopulation NFE AF = 0.00346 (235/67992). AF 95% confidence interval is 0.00309. There are 0 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003896.4. 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
	ST3GAL5	NM_003896.4	MANE Select	c.*140delA		3_prime_UTR	Exon 7 of 7	NP_003887.3
	ST3GAL5	NM_001042437.2		c.*140delA		3_prime_UTR	Exon 7 of 7	NP_001035902.1	Q9UNP4-3
	ST3GAL5	NM_001354227.2		c.*140delA		3_prime_UTR	Exon 8 of 8	NP_001341156.1	A0A0S2Z4S6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ST3GAL5	ENST00000638572.2	TSL:1 MANE Select	c.*140delA		3_prime_UTR	Exon 7 of 7	ENSP00000491316.1	Q9UNP4-1
	ST3GAL5	ENST00000393808.8	TSL:1	c.*140delA		3_prime_UTR	Exon 7 of 7	ENSP00000377397.3	Q9UNP4-3
	ST3GAL5	ENST00000393805.6	TSL:1	c.*140delA		3_prime_UTR	Exon 7 of 7	ENSP00000377394.1	Q9UNP4-2

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00346

Gnomad OTH AF: 0.00240

GnomAD4 exome AF: 0.00311 AC: 3699 AN: 1189148 Hom.: 7 Cov.: 17 AF XY: 0.00292 AC XY: 1720 AN XY: 589142

African (AFR) AF: 0.000650 AC: 17 AN: 26172

American (AMR) AF: 0.00132 AC: 37 AN: 28132

Ashkenazi Jewish (ASJ) AF: 0.0000450 AC: 1 AN: 22232

East Asian (EAS) AF: 0.00 AC: 0 AN: 34640

South Asian (SAS) AF: 0.000201 AC: 14 AN: 69484

European-Finnish (FIN) AF: 0.000213 AC: 8 AN: 37614

Middle Eastern (MID) AF: 0.00197 AC: 8 AN: 4068

European-Non Finnish (NFE) AF: 0.00382 AC: 3500 AN: 916262

Other (OTH) AF: 0.00226 AC: 114 AN: 50544

GnomAD4 genome AF: 0.00186 AC: 283 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74420

African (AFR) AF: 0.000723 AC: 30 AN: 41518

American (AMR) AF: 0.000589 AC: 9 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00346 AC: 235 AN: 67992

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.000271 Hom.: 0

Bravo AF: 0.00208

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	GM3 synthase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.040
Mutation Taster		=100/0	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: rs550737011; hg19: chr2-86067126; COSMIC: COSV101062221; COSMIC: COSV101062221;