13-36326691-T-C

Variant names:

• chr13-36326691-T-C
• rs148833652
• NM_015087.5:c.1172A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015087.5(SPART):​c.1172A>G​(p.Asp391Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,612,882 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D391V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (8 hom.)
• Consequence: SPART NM_015087.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5 O:1
• Conservation: PhyloP100: 1.05
• Publications: 3 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: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005650997).
• BP6: Variant 13-36326691-T-C is Benign according to our data. Variant chr13-36326691-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216687.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00118 (180/152214) while in subpopulation NFE AF = 0.00229 (156/68010). AF 95% confidence interval is 0.002. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.1172A>G	p.Asp391Gly	missense	Exon 5 of 9	NP_055902.1	Q8N0X7
	SPART	NM_001142294.2		c.1172A>G	p.Asp391Gly	missense	Exon 5 of 9	NP_001135766.1	Q8N0X7
	SPART	NM_001142295.2		c.1172A>G	p.Asp391Gly	missense	Exon 5 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.1172A>G	p.Asp391Gly	missense	Exon 5 of 9	ENSP00000406061.2	Q8N0X7
	SPART	ENST00000451493.5	TSL:1	c.1172A>G	p.Asp391Gly	missense	Exon 5 of 9	ENSP00000414147.1	Q8N0X7
	SPART	ENST00000494062.2	TSL:1	c.1172A>G	p.Asp391Gly	missense	Exon 6 of 10	ENSP00000473599.1	Q8N0X7

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00114 AC: 285 AN: 251062 AF XY: 0.00115

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.00206 AC: 3002 AN: 1460668 Hom.: 8 Cov.: 31 AF XY: 0.00199 AC XY: 1445 AN XY: 726656

African (AFR) AF: 0.000359 AC: 12 AN: 33442

American (AMR) AF: 0.000157 AC: 7 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86206

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5214

European-Non Finnish (NFE) AF: 0.00261 AC: 2904 AN: 1111748

Other (OTH) AF: 0.00111 AC: 67 AN: 60304

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000887 AC XY: 66 AN XY: 74430

African (AFR) AF: 0.000457 AC: 19 AN: 41532

American (AMR) AF: 0.000327 AC: 5 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00229 AC: 156 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00192 Hom.: 5

Bravo AF: 0.00120

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00103 AC: 125

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00255

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (5)
-	2	-	Troyer syndrome (2)
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	SPART-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.60	T
PhyloP100		1.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.16
Sift	Benign	0.37	T
Sift4G	Benign	0.41	T
Polyphen		0.0020	B
Vest4		0.060
MVP		0.75
MPC		0.095
ClinPred		0.0083	T
GERP RS		-0.43
Varity_R		0.062
gMVP		0.37
Mutation Taster		=92/8	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: rs148833652; hg19: chr13-36900828;