rs121909484

Variant names:

• chr3-155853659-A-C
• rs121909484
• NM_004733.4:c.339T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004733.4(SLC33A1):​c.339T>G​(p.Ser113Arg) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC33A1 NM_004733.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.07

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 3-155853659-A-C is Pathogenic according to our data. Variant chr3-155853659-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 6132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-155853659-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC33A1	NM_004733.4	c.339T>G	p.Ser113Arg	missense_variant	Exon 1 of 6	ENST00000643144.2	NP_004724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC33A1	ENST00000643144.2	c.339T>G	p.Ser113Arg	missense_variant	Exon 1 of 6		NM_004733.4	ENSP00000496241.1
ENSG00000284952	ENST00000643876.1	n.339T>G		non_coding_transcript_exon_variant	Exon 1 of 10			ENSP00000495323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary spastic paraplegia 42 Pathogenic:1

Feb 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D;D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.93	.;.;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.1	M;M;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.8	D;.;D;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Pathogenic	0.0	D;.;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.98
MutPred		0.88		Gain of methylation at S113 (P = 0.0133);Gain of methylation at S113 (P = 0.0133);Gain of methylation at S113 (P = 0.0133);Gain of methylation at S113 (P = 0.0133);
MVP		0.92
MPC		2.3
ClinPred		1.0	D
GERP RS		0.14
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909484; hg19: chr3-155571448;