rs312262747

Variant names:

• chr15-44620307-TG-T
• rs312262747
• NM_025137.4:c.2716delC

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Strong

The NM_025137.4(SPG11):c.2716delC (p.Gln906SerfsTer15) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.0000041 (AC=6) in the gnomAD database across 1,461,806 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00003. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SPG11 NM_025137.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 3.61
• 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: Genomics England PanelApp, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Illumina
• 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 15 of 40) at amino acid 906 of 2443, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~919 amino acids (1524 amino acids lost).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00003 — very rare for AR gene (threshold 0.001) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SPG11 NM_025137.4	MANE Select	c.2716delC p.Gln906SerfsTer15	frameshift	Exon 15 of 40	Prot: NP_079413.3
	SPG11 NM_001411132.1		c.2716delC p.Gln906SerfsTer15	frameshift	Exon 15 of 40	Prot: NP_001398061.1 UniProt:
	SPG11 NM_001160227.2		c.2716delC p.Gln906SerfsTer15	frameshift	Exon 15 of 38	Prot: NP_001153699.1 UniProt:

SPG11 NM_025137.4

MANE Select

HGVSc / HGVSpc.2716delCp.Gln906SerfsTer15

Exon rankExon 15 of 40

frameshift

Prot: NP_079413.3

SPG11 NM_001411132.1

HGVSc / HGVSpc.2716delCp.Gln906SerfsTer15

Exon rankExon 15 of 40

frameshift

Prot: NP_001398061.1UniProt: A0A804HID9

SPG11 NM_001160227.2

HGVSc / HGVSpc.2716delCp.Gln906SerfsTer15

Exon rankExon 15 of 38

frameshift

Prot: NP_001153699.1UniProt: Q96JI7-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SPG11 ENST00000261866.12	TSL:1MANE Select	c.2716delC p.Gln906SerfsTer15	frameshift	Exon 15 of 40	Prot: ENSP00000261866.7 UniProt:
	SPG11 ENST00000535302.6	TSL:1	c.2716delC p.Gln906SerfsTer15	frameshift	Exon 15 of 38	Prot: ENSP00000445278.2 UniProt:
	SPG11 ENST00000427534.6	TSL:1	c.2716delC p.Gln906SerfsTer15	frameshift	Exon 15 of 37	Prot: ENSP00000396110.2 UniProt:

SPG11 ENST00000261866.12

TSL:1MANE Select

HGVSc / HGVSpc.2716delCp.Gln906SerfsTer15

Exon rankExon 15 of 40

frameshift

Prot: ENSP00000261866.7UniProt: Q96JI7-1

SPG11 ENST00000535302.6

TSL:1

HGVSc / HGVSpc.2716delCp.Gln906SerfsTer15

Exon rankExon 15 of 38

frameshift

Prot: ENSP00000445278.2UniProt: Q96JI7-3

SPG11 ENST00000427534.6

TSL:1

HGVSc / HGVSpc.2716delCp.Gln906SerfsTer15

Exon rankExon 15 of 37

frameshift

Prot: ENSP00000396110.2UniProt: F8W8Y5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251404	Cov:
GnomAD4 exome	AF: 0.00000410	AC:6	Hom:0	AN:1461806	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Hereditary spastic paraplegia 11 (5)
2	-	-	not provided (2)
1	-	-	Hereditary spastic paraplegia (1)
1	-	-	Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Benign	3.6

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs312262747;

hg19: chr15-44912505;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar