rs35932349

Variant names:

• chr15-44572696-C-T
• rs35932349
• NM_025137.4:c.6330G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_025137.4(SPG11):​c.6330G>A​(p.Gly2110Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,046 control chromosomes in the GnomAD database, including 337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (55 hom., cov: 31)
  • Exomes 𝑓: 0.0099 (282 hom.)
• Consequence: SPG11 NM_025137.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.566
• Publications: 9 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: G2P, ClinGen, Illumina, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 15-44572696-C-T is Benign according to our data. Variant chr15-44572696-C-T is described in ClinVar as Benign. ClinVar VariationId is 130367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.566 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0902 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	NM_025137.4	MANE Select	c.6330G>A	p.Gly2110Gly	synonymous	Exon 33 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.6186G>A	p.Gly2062Gly	synonymous	Exon 33 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.5991G>A	p.Gly1997Gly	synonymous	Exon 31 of 38	NP_001153699.1	Q96JI7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	ENST00000261866.12	TSL:1 MANE Select	c.6330G>A	p.Gly2110Gly	synonymous	Exon 33 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.5991G>A	p.Gly1997Gly	synonymous	Exon 31 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.6330G>A	p.Gly2110Gly	synonymous	Exon 33 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2178 AN: 152046 Hom.: 53 Cov.: 31

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0969

Gnomad SAS AF: 0.0429

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00543

Gnomad OTH AF: 0.00910

GnomAD2 exomes AF: 0.0180 AC: 4520 AN: 251470 AF XY: 0.0179

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.0944

Gnomad FIN exome AF: 0.0329

Gnomad NFE exome AF: 0.00512

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.00994 AC: 14529 AN: 1461882 Hom.: 282 Cov.: 32 AF XY: 0.0105 AC XY: 7650 AN XY: 727242

African (AFR) AF: 0.0158 AC: 529 AN: 33480

American (AMR) AF: 0.00291 AC: 130 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00650 AC: 170 AN: 26136

East Asian (EAS) AF: 0.0736 AC: 2920 AN: 39700

South Asian (SAS) AF: 0.0331 AC: 2858 AN: 86258

European-Finnish (FIN) AF: 0.0320 AC: 1709 AN: 53420

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.00487 AC: 5413 AN: 1112002

Other (OTH) AF: 0.0127 AC: 768 AN: 60394

GnomAD4 genome AF: 0.0144 AC: 2194 AN: 152164 Hom.: 55 Cov.: 31 AF XY: 0.0173 AC XY: 1288 AN XY: 74382

African (AFR) AF: 0.0150 AC: 622 AN: 41520

American (AMR) AF: 0.00340 AC: 52 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.0972 AC: 502 AN: 5166

South Asian (SAS) AF: 0.0427 AC: 206 AN: 4826

European-Finnish (FIN) AF: 0.0353 AC: 374 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00543 AC: 369 AN: 68000

Other (OTH) AF: 0.0133 AC: 28 AN: 2110

Alfa AF: 0.00621 Hom.: 8

Bravo AF: 0.0128

Asia WGS AF: 0.0740 AC: 256 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Hereditary spastic paraplegia 11 (4)
-	-	1	Amyotrophic lateral sclerosis type 5 (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2X (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	6.1
DANN	Benign	0.72
PhyloP100		0.57
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs35932349; hg19: chr15-44864894; COSMIC: COSV55999572; COSMIC: COSV55999572;