12-22201867-G-T

Position:

• chr12-22201867-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003034.4(ST8SIA1):​c.756C>A​(p.Asn252Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ST8SIA1 NM_003034.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85

Genes affected

ST8SIA1 (HGNC:10869): (ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1) Gangliosides are membrane-bound glycosphingolipids containing sialic acid. Ganglioside GD3 is known to be important for cell adhesion and growth of cultured malignant cells. The protein encoded by this gene is a type II membrane protein that catalyzes the transfer of sialic acid from CMP-sialic acid to GM3 to produce gangliosides GD3 and GT3. The encoded protein may be found in the Golgi apparatus and is a member of glycosyltransferase family 29. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ST8SIA1	NM_003034.4	c.756C>A	p.Asn252Lys	missense_variant	5/5	ENST00000396037.9	NP_003025.1
ST8SIA1	NM_001304450.2	c.327C>A	p.Asn109Lys	missense_variant	4/4		NP_001291379.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ST8SIA1	ENST00000396037.9	c.756C>A	p.Asn252Lys	missense_variant	5/5	1	NM_003034.4	ENSP00000379353.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2024

The c.756C>A (p.N252K) alteration is located in exon 5 (coding exon 5) of the ST8SIA1 gene. This alteration results from a C to A substitution at nucleotide position 756, causing the asparagine (N) at amino acid position 252 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.9	M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.68		Loss of stability (P = 0.0254);
MVP		0.79
MPC		1.4
ClinPred		0.99	D
GERP RS		2.4
Varity_R		0.55
gMVP		0.96

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-22354801;