rs74868982

Variant names:

• chr13-36301911-T-A
• rs74868982
• NM_015087.5:c.*2454A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_015087.5(SPART):​c.*2454A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 152,246 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPART NM_015087.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.672
• Publications: 0 publications found

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]

SPART Gene-Disease associations (from GenCC):

• Troyer syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00152 (232/152246) while in subpopulation NFE AF = 0.00253 (172/68030). AF 95% confidence interval is 0.00222. There are 2 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015087.5. 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
	SPART	NM_015087.5	MANE Select	c.*2454A>T		3_prime_UTR	Exon 9 of 9	NP_055902.1	Q8N0X7
	SPART	NM_001142294.2		c.*2454A>T		3_prime_UTR	Exon 9 of 9	NP_001135766.1	Q8N0X7
	SPART	NM_001142295.2		c.*2454A>T		3_prime_UTR	Exon 9 of 9	NP_001135767.1	Q8N0X7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPART	ENST00000438666.7	TSL:1 MANE Select	c.*2454A>T		3_prime_UTR	Exon 9 of 9	ENSP00000406061.2	Q8N0X7
	SPART	ENST00000451493.5	TSL:1	c.*2454A>T		3_prime_UTR	Exon 9 of 9	ENSP00000414147.1	Q8N0X7
	SPART	ENST00000355182.8	TSL:5	c.*2454A>T		3_prime_UTR	Exon 9 of 9	ENSP00000347314.4	Q8N0X7

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152128 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.000957

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152246 Hom.: 2 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74442

African (AFR) AF: 0.000313 AC: 13 AN: 41544

American (AMR) AF: 0.000785 AC: 12 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00253 AC: 172 AN: 68030

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.00142

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Troyer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.6
DANN	Benign	0.80
PhyloP100		0.67

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: rs74868982; hg19: chr13-36876048;