rs148399669

Positions:

• chr13-36335756-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_015087.5(SPART):​c.75A>G​(p.Leu25=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,614,062 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (16 hom.)
• Consequence: SPART NM_015087.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.05

Genes affected

SPART (HGNC:18514): (spartin) This gene encodes a protein containing a MIT (Microtubule Interacting and Trafficking molecule) domain, and is implicated in regulating endosomal trafficking and mitochondria function. The protein localizes to mitochondria and partially co-localizes with microtubules. Stimulation with epidermal growth factor (EGF) results in protein translocation to the plasma membrane, and the protein functions in the degradation and intracellular trafficking of EGF receptor. Multiple alternatively spliced variants, encoding the same protein, have been identified. Mutations associated with this gene cause autosomal recessive spastic paraplegia 20 (Troyer syndrome). [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 13-36335756-T-C is Benign according to our data. Variant chr13-36335756-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215884.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00116 (176/152316) while in subpopulation NFE AF= 0.000911 (62/68020). AF 95% confidence interval is 0.000729. There are 3 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPART	NM_015087.5	c.75A>G	p.Leu25=	synonymous_variant	2/9	ENST00000438666.7	NP_055902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPART	ENST00000438666.7	c.75A>G	p.Leu25=	synonymous_variant	2/9	1	NM_015087.5	ENSP00000406061	P1

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152198 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00153 AC: 384 AN: 250978 Hom.: 4 AF XY: 0.00146 AC XY: 198 AN XY: 135636

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00120 AC: 1758 AN: 1461746 Hom.: 16 Cov.: 32 AF XY: 0.00121 AC XY: 879 AN XY: 727168

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.0209

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000746

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152316 Hom.: 3 Cov.: 32 AF XY: 0.00115 AC XY: 86 AN XY: 74478

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00255 Hom.: 1

Bravo AF: 0.00114

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SPART: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2021	- -

Troyer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 15, 2021

- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.3
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs148399669; hg19: chr13-36909893;