2-85861188-T-C

Variant names:

• chr2-85861188-T-C
• rs1138484
• NM_003896.4:c.311A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003896.4(ST3GAL5):​c.311A>G​(p.His104Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,594,414 control chromosomes in the GnomAD database, including 35,802 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H104L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (2910 hom., cov: 31)
  • Exomes 𝑓: 0.21 (32892 hom.)
• Consequence: ST3GAL5 NM_003896.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.10
• Publications: 27 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035613477).
• BP6: Variant 2-85861188-T-C is Benign according to our data. Variant chr2-85861188-T-C is described in ClinVar as Benign. ClinVar VariationId is 130382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

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.311A>G	p.His104Arg	missense	Exon 3 of 7	NP_003887.3
	ST3GAL5	NM_001042437.2		c.242A>G	p.His81Arg	missense	Exon 3 of 7	NP_001035902.1	Q9UNP4-3
	ST3GAL5	NM_001354227.2		c.227A>G	p.His76Arg	missense	Exon 4 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.311A>G	p.His104Arg	missense	Exon 3 of 7	ENSP00000491316.1	Q9UNP4-1
	ST3GAL5	ENST00000393808.8	TSL:1	c.242A>G	p.His81Arg	missense	Exon 3 of 7	ENSP00000377397.3	Q9UNP4-3
	ST3GAL5	ENST00000393805.6	TSL:1	c.227A>G	p.His76Arg	missense	Exon 3 of 7	ENSP00000377394.1	Q9UNP4-2

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27292 AN: 152132 Hom.: 2913 Cov.: 31

Gnomad AFR AF: 0.0771

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.217 AC: 54473 AN: 251086 AF XY: 0.226

Gnomad AFR exome AF: 0.0726

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.321

Gnomad FIN exome AF: 0.252

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.212

GnomAD4 exome AF: 0.209 AC: 301568 AN: 1442164 Hom.: 32892 Cov.: 29 AF XY: 0.213 AC XY: 152873 AN XY: 718782

African (AFR) AF: 0.0707 AC: 2344 AN: 33170

American (AMR) AF: 0.150 AC: 6701 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3934 AN: 26020

East Asian (EAS) AF: 0.271 AC: 10706 AN: 39548

South Asian (SAS) AF: 0.315 AC: 26980 AN: 85738

European-Finnish (FIN) AF: 0.256 AC: 13639 AN: 53254

Middle Eastern (MID) AF: 0.166 AC: 887 AN: 5328

European-Non Finnish (NFE) AF: 0.205 AC: 224531 AN: 1094646

Other (OTH) AF: 0.198 AC: 11846 AN: 59758

GnomAD4 genome AF: 0.179 AC: 27280 AN: 152250 Hom.: 2910 Cov.: 31 AF XY: 0.184 AC XY: 13729 AN XY: 74436

African (AFR) AF: 0.0769 AC: 3197 AN: 41566

American (AMR) AF: 0.166 AC: 2542 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 526 AN: 3470

East Asian (EAS) AF: 0.309 AC: 1601 AN: 5184

South Asian (SAS) AF: 0.343 AC: 1652 AN: 4816

European-Finnish (FIN) AF: 0.242 AC: 2566 AN: 10588

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14564 AN: 68004

Other (OTH) AF: 0.190 AC: 401 AN: 2116

Alfa AF: 0.197 Hom.: 13073

Bravo AF: 0.165

TwinsUK AF: 0.205 AC: 760

ALSPAC AF: 0.214 AC: 826

ESP6500AA AF: 0.0758 AC: 334

ESP6500EA AF: 0.198 AC: 1705

ExAC AF: 0.222 AC: 26999

Asia WGS AF: 0.262 AC: 909 AN: 3478

EpiCase AF: 0.203

EpiControl AF: 0.209

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	GM3 synthase deficiency (3)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.23
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.4	N
PhyloP100		1.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.082
Sift	Benign	1.0	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.033
MPC		0.37
ClinPred		0.000012	T
GERP RS		5.0
Varity_R		0.039
gMVP		0.54
Mutation Taster		=98/2	polymorphism (auto)

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: rs1138484; hg19: chr2-86088311; COSMIC: COSV60385902; COSMIC: COSV60385902;