rs74578336

Variant names:

• chr3-155853671-T-C
• rs74578336
• NM_004733.4:c.327A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004733.4(SLC33A1):​c.327A>G​(p.Gln109Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,614,172 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (76 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (72 hom.)
• Consequence: SLC33A1 NM_004733.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00300
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, PanelApp Australia
• hereditary spastic paraplegia 42

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

ENSG00000284952 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 3-155853671-T-C is Benign according to our data. Variant chr3-155853671-T-C is described in ClinVar as Benign. ClinVar VariationId is 343881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC33A1	NM_004733.4	MANE Select	c.327A>G	p.Gln109Gln	synonymous	Exon 1 of 6	NP_004724.1	O00400
	SLC33A1	NM_001190992.2		c.327A>G	p.Gln109Gln	synonymous	Exon 1 of 7	NP_001177921.1	O00400
	SLC33A1	NM_001363883.1		c.327A>G	p.Gln109Gln	synonymous	Exon 1 of 4	NP_001350812.1	A0A2R8YF57

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC33A1	ENST00000643144.2	MANE Select	c.327A>G	p.Gln109Gln	synonymous	Exon 1 of 6	ENSP00000496241.1	O00400
	SLC33A1	ENST00000359479.7	TSL:1	c.327A>G	p.Gln109Gln	synonymous	Exon 1 of 7	ENSP00000352456.3	O00400
	ENSG00000284952	ENST00000643876.1		n.327A>G		non_coding_transcript_exon	Exon 1 of 10	ENSP00000495323.1	A0A2R8Y6H1

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2692 AN: 152192 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.0609

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00500 AC: 1257 AN: 251388 AF XY: 0.00377

Gnomad AFR exome AF: 0.0658

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00227 AC: 3317 AN: 1461862 Hom.: 72 Cov.: 32 AF XY: 0.00199 AC XY: 1449 AN XY: 727232

African (AFR) AF: 0.0650 AC: 2175 AN: 33480

American (AMR) AF: 0.00378 AC: 169 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.000566 AC: 629 AN: 1112002

Other (OTH) AF: 0.00452 AC: 273 AN: 60396

GnomAD4 genome AF: 0.0177 AC: 2696 AN: 152310 Hom.: 76 Cov.: 32 AF XY: 0.0165 AC XY: 1228 AN XY: 74466

African (AFR) AF: 0.0609 AC: 2531 AN: 41570

American (AMR) AF: 0.00680 AC: 104 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68030

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.00766 Hom.: 21

Bravo AF: 0.0207

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not specified (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.1
DANN	Benign	0.62
PhyloP100		0.0030
PromoterAI		0.030	Neutral
Mutation Taster		=98/2	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: rs74578336; hg19: chr3-155571460;