3-155853486-T-A

Variant names:

• chr3-155853486-T-A
• rs3804769
• NM_004733.4:c.512A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004733.4(SLC33A1):​c.512A>T​(p.Asp171Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 13/22 in silico tools predict a benign 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. D171G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC33A1 NM_004733.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.63
• Publications: 23 publications found

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]

SLC33A1 Gene-Disease associations (from GenCC):

• Huppke-Brendel syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 42

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Illumina, Orphanet

ENSG00000284952 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004733.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC33A1	NM_004733.4	MANE Select	c.512A>T	p.Asp171Val	missense	Exon 1 of 6	NP_004724.1
	SLC33A1	NM_001190992.2		c.512A>T	p.Asp171Val	missense	Exon 1 of 7	NP_001177921.1
	SLC33A1	NM_001363883.1		c.512A>T	p.Asp171Val	missense	Exon 1 of 4	NP_001350812.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC33A1	ENST00000643144.2	MANE Select	c.512A>T	p.Asp171Val	missense	Exon 1 of 6	ENSP00000496241.1
	SLC33A1	ENST00000359479.7	TSL:1	c.512A>T	p.Asp171Val	missense	Exon 1 of 7	ENSP00000352456.3
	ENSG00000284952	ENST00000643876.1		n.512A>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000495323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.056
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Benign	0.071	T
Sift4G	Benign	0.23	T
Polyphen		0.010	B
Vest4		0.20
MutPred		0.30		Loss of disorder (P = 0.0133)
MVP		0.83
MPC		1.5
ClinPred		0.79	D
GERP RS		5.4
PromoterAI		-0.0080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.080
gMVP		0.61
Mutation Taster		=87/13	polymorphism

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: rs3804769; hg19: chr3-155571275;