chr3-155828325-A-G

Position:

• chr3-155828325-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004733.4(SLC33A1):​c.1535T>C​(p.Val512Ala) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: SLC33A1 NM_004733.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.18

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC33A1	NM_004733.4	c.1535T>C	p.Val512Ala	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.1535T>C	p.Val512Ala	missense_variant	6/6		NM_004733.4	ENSP00000496241.1
ENSG00000284952	ENST00000643876.1	n.*857T>C		non_coding_transcript_exon_variant	6/10			ENSP00000495323.1
ENSG00000284952	ENST00000643876.1	n.*857T>C		3_prime_UTR_variant	6/10			ENSP00000495323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2021

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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces valine with alanine at codon 512 of the SLC33A1 protein (p.Val512Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SLC33A1-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;T;.;.
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;.;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.2	M;M;M;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.4	D;.;D;.;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;.;D;.;D
Sift4G	Uncertain	0.051	T;.;T;.;D
Polyphen		0.77	P;P;P;.;.
Vest4		0.68
MutPred		0.42		Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);.;.;
MVP		0.89
MPC		1.1
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.58
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr3-155546114;