18-46680100-A-G

Variant names:

• chr18-46680100-A-G
• rs1568246567
• NM_013305.6:c.1073T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_013305.6(ST8SIA5):​c.1073T>C​(p.Leu358Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L358Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ST8SIA5 NM_013305.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.22
• Publications: 0 publications found

Genes affected

ST8SIA5 (HGNC:17827): (ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 5) The protein encoded by this gene is a type II membrane protein that may be present in the Golgi apparatus. The encoded protein, which is a member of glycosyltransferase family 29, may be involved in the synthesis of gangliosides GD1c, GT1a, GQ1b, and GT3 from GD1a, GT1b, GM1b, and GD3, respectively. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013305.6. 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
	ST8SIA5	NM_013305.6	MANE Select	c.1073T>C	p.Leu358Pro	missense	Exon 7 of 7	NP_037437.2
	ST8SIA5	NM_001307986.2		c.1181T>C	p.Leu394Pro	missense	Exon 8 of 8	NP_001294915.1	O15466-2
	ST8SIA5	NM_001307987.2		c.980T>C	p.Leu327Pro	missense	Exon 6 of 6	NP_001294916.1	F5H8D1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ST8SIA5	ENST00000315087.12	TSL:1 MANE Select	c.1073T>C	p.Leu358Pro	missense	Exon 7 of 7	ENSP00000321343.6	O15466-1
	ST8SIA5	ENST00000538168.5	TSL:2	c.1181T>C	p.Leu394Pro	missense	Exon 8 of 8	ENSP00000445492.1	O15466-2
	ST8SIA5	ENST00000911623.1		c.1166T>C	p.Leu389Pro	missense	Exon 8 of 8	ENSP00000581682.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461776 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

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

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.2
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.71
MutPred		0.80		Loss of stability (P = 0.0052)
MVP		0.67
MPC		1.8
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.93
gMVP		0.94
Mutation Taster		=16/84	disease causing

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: rs1568246567; hg19: chr18-44260063;