chr2-85839729-A-G

Variant names:

• chr2-85839729-A-G
• rs112372963
• NM_003896.4:c.*415T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_003896.4(ST3GAL5):​c.*415T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 308,454 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (2 hom.)
• Consequence: ST3GAL5 NM_003896.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.21
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00344 (524/152354) while in subpopulation NFE AF = 0.00611 (416/68034). AF 95% confidence interval is 0.00563. There are 2 homozygotes in GnomAd4. There are 238 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 GnomAd4 at 2 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.*415T>C		3_prime_UTR	Exon 7 of 7	NP_003887.3
	ST3GAL5	NM_001042437.2		c.*415T>C		3_prime_UTR	Exon 7 of 7	NP_001035902.1	Q9UNP4-3
	ST3GAL5	NM_001354227.2		c.*415T>C		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.*415T>C		3_prime_UTR	Exon 7 of 7	ENSP00000491316.1	Q9UNP4-1
	ST3GAL5	ENST00000393808.8	TSL:1	c.*415T>C		3_prime_UTR	Exon 7 of 7	ENSP00000377397.3	Q9UNP4-3
	ST3GAL5	ENST00000393805.6	TSL:1	c.*415T>C		3_prime_UTR	Exon 7 of 7	ENSP00000377394.1	Q9UNP4-2

Frequencies

GnomAD3 genomes AF: 0.00345 AC: 525 AN: 152236 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00613

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00422 AC: 659 AN: 156100 Hom.: 2 Cov.: 0 AF XY: 0.00374 AC XY: 320 AN XY: 85630

African (AFR) AF: 0.000254 AC: 1 AN: 3942

American (AMR) AF: 0.000868 AC: 5 AN: 5762

Ashkenazi Jewish (ASJ) AF: 0.00110 AC: 4 AN: 3634

East Asian (EAS) AF: 0.00 AC: 0 AN: 6108

South Asian (SAS) AF: 0.000436 AC: 13 AN: 29792

European-Finnish (FIN) AF: 0.00324 AC: 25 AN: 7718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 546

European-Non Finnish (NFE) AF: 0.00640 AC: 583 AN: 91052

Other (OTH) AF: 0.00371 AC: 28 AN: 7546

GnomAD4 genome AF: 0.00344 AC: 524 AN: 152354 Hom.: 2 Cov.: 32 AF XY: 0.00319 AC XY: 238 AN XY: 74504

African (AFR) AF: 0.00115 AC: 48 AN: 41584

American (AMR) AF: 0.000719 AC: 11 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00611 AC: 416 AN: 68034

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00410 Hom.: 0

Bravo AF: 0.00298

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	GM3 synthase deficiency (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.5
DANN	Benign	0.57
PhyloP100		1.2

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: rs112372963; hg19: chr2-86066852;