rs139532029

Variant names:

• chr15-44606059-A-G
• rs139532029
• NM_025137.4:c.3486T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_025137.4(SPG11):​c.3486T>C​(p.Phe1162Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000591 in 1,613,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: SPG11 NM_025137.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.31
• Publications: 1 publications found

Genes affected

SPG11 (HGNC:11226): (SPG11 vesicle trafficking associated, spatacsin) The protein encoded by this gene is a potential transmembrane protein that is phosphorylated upon DNA damage. Defects in this gene are a cause of spastic paraplegia type 11 (SPG11). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

SPG11 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 11

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina, G2P
• amyotrophic lateral sclerosis type 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Charcot-Marie-Tooth disease axonal type 2X

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 15-44606059-A-G is Benign according to our data. Variant chr15-44606059-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 466521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000612 (895/1461478) while in subpopulation NFE AF = 0.000767 (853/1111776). AF 95% confidence interval is 0.000724. There are 0 homozygotes in GnomAdExome4. There are 453 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025137.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	NM_025137.4	MANE Select	c.3486T>C	p.Phe1162Phe	synonymous	Exon 20 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.3486T>C	p.Phe1162Phe	synonymous	Exon 20 of 40	NP_001398061.1
	SPG11	NM_001160227.2		c.3486T>C	p.Phe1162Phe	synonymous	Exon 20 of 38	NP_001153699.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	ENST00000261866.12	TSL:1 MANE Select	c.3486T>C	p.Phe1162Phe	synonymous	Exon 20 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.3486T>C	p.Phe1162Phe	synonymous	Exon 20 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.3486T>C	p.Phe1162Phe	synonymous	Exon 20 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000750

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000382 AC: 96 AN: 251354 AF XY: 0.000397

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000800

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000612 AC: 895 AN: 1461478 Hom.: 0 Cov.: 30 AF XY: 0.000623 AC XY: 453 AN XY: 727050

African (AFR) AF: 0.0000897 AC: 3 AN: 33460

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000767 AC: 853 AN: 1111776

Other (OTH) AF: 0.000547 AC: 33 AN: 60378

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74486

African (AFR) AF: 0.0000240 AC: 1 AN: 41590

American (AMR) AF: 0.000392 AC: 6 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

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

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68024

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

Alfa AF: 0.000549 Hom.: 0

Bravo AF: 0.000397

EpiCase AF: 0.00147

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Hereditary spastic paraplegia 11 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	SPG11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs139532029; hg19: chr15-44898257; COSMIC: COSV99970001;