Genetic Variant NM_004733.4:c.614dupT (chr3-155853383-T-TA) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_004733.4(SLC33A1):c.614dupT(p.Leu205PhefsTer32) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SLC33A1
NM_004733.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 9.12

Publications

0 publications found

Variant links:

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

SLC33A1 links:

ENSG00000284952 (HGNC:):

ENSG00000284952 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-155853383-T-TA is Pathogenic according to our data. Variant chr3-155853383-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 30378.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC33A1	NM_004733.4 link	c.614dupT	p.Leu205PhefsTer32	frameshift_variant	Exon 1 of 6	ENST00000643144.2	NP_004724.1	O00400

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC33A1	ENST00000643144.2 link	c.614dupT	p.Leu205PhefsTer32	frameshift_variant	Exon 1 of 6		NM_004733.4	ENSP00000496241.1		O00400
ENSG00000284952	ENST00000643876.1 link	n.614dupT		non_coding_transcript_exon_variant	Exon 1 of 10			ENSP00000495323.1		A0A2R8Y6H1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Huppke-Brendel syndrome

Pathogenic:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 13, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.1

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over