3-155828214-T-C

Position:

• chr3-155828214-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004733.4(SLC33A1):​c.1646A>G​(p.Asn549Ser) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC33A1 NM_004733.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.03

Genes affected

SLC33A1 (HGNC:95): (solute carrier family 33 member 1) The protein encoded by this gene is required for the formation of O-acetylated (Ac) gangliosides. The encoded protein is predicted to contain 6 to 10 transmembrane domains, and a leucine zipper motif in transmembrane domain III. Defects in this gene have been reported to cause spastic paraplegia autosomal dominant type 42 (SPG42) in one Chinese family, but not in similar patients of European descent. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2010]

ENSG00000284952 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14327806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC33A1	NM_004733.4	c.1646A>G	p.Asn549Ser	missense_variant	6/6	ENST00000643144.2	NP_004724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC33A1	ENST00000643144.2	c.1646A>G	p.Asn549Ser	missense_variant	6/6		NM_004733.4	ENSP00000496241.1
ENSG00000284952	ENST00000643876.1	n.*968A>G		non_coding_transcript_exon_variant	6/10			ENSP00000495323.1
ENSG00000284952	ENST00000643876.1	n.*968A>G		3_prime_UTR_variant	6/10			ENSP00000495323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 22, 2020

This variant has not been reported in the literature in individuals with SLC33A1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 549 of the SLC33A1 protein (p.Asn549Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 07, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.6
DANN	Benign	0.61
DEOGEN2	Benign	0.026	T;T;T;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.81	.;.;T;T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L;L;L;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.19	N;.;N;.;N
REVEL	Benign	0.060
Sift	Benign	0.21	T;.;T;.;T
Sift4G	Benign	0.41	T;.;T;.;T
Polyphen		0.0	B;B;B;.;.
Vest4		0.17
MutPred		0.24		Gain of MoRF binding (P = 0.0984);Gain of MoRF binding (P = 0.0984);Gain of MoRF binding (P = 0.0984);.;.;
MVP		0.62
MPC		0.31
ClinPred		0.17	T
GERP RS		3.4
Varity_R		0.027
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1752264956; hg19: chr3-155546003;