rs544136842

Variant names:

• chr15-44663588-C-G
• rs544136842
• NM_025137.4:c.60G>C

Your query was ambiguous. Multiple possible variants found:

• chr15-44663588-C-G
• chr15-44663588-C-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_025137.4(SPG11):​c.60G>C​(p.Ala20Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,596,660 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A20A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: SPG11 NM_025137.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.662
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 15-44663588-C-G is Benign according to our data. Variant chr15-44663588-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241597.
• BP7: Synonymous conserved (PhyloP=-0.662 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000109 (157/1444298) while in subpopulation MID AF = 0.00087 (5/5746). AF 95% confidence interval is 0.000608. There are 1 homozygotes in GnomAdExome4. There are 103 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	NM_025137.4	MANE Select	c.60G>C	p.Ala20Ala	synonymous	Exon 1 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.60G>C	p.Ala20Ala	synonymous	Exon 1 of 40	NP_001398061.1
	SPG11	NM_001160227.2		c.60G>C	p.Ala20Ala	synonymous	Exon 1 of 38	NP_001153699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	ENST00000261866.12	TSL:1 MANE Select	c.60G>C	p.Ala20Ala	synonymous	Exon 1 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.60G>C	p.Ala20Ala	synonymous	Exon 1 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.60G>C	p.Ala20Ala	synonymous	Exon 1 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000181 AC: 38 AN: 210242 AF XY: 0.000240

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000620

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000119

Gnomad OTH exome AF: 0.000188

GnomAD4 exome AF: 0.000109 AC: 157 AN: 1444298 Hom.: 1 Cov.: 32 AF XY: 0.000144 AC XY: 103 AN XY: 717742

African (AFR) AF: 0.00 AC: 0 AN: 33312

American (AMR) AF: 0.0000462 AC: 2 AN: 43278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25702

East Asian (EAS) AF: 0.00 AC: 0 AN: 39246

South Asian (SAS) AF: 0.000757 AC: 64 AN: 84566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46128

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5746

European-Non Finnish (NFE) AF: 0.0000696 AC: 77 AN: 1106550

Other (OTH) AF: 0.000151 AC: 9 AN: 59770

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152362 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary spastic paraplegia 11 (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	3.8
DANN	Benign	0.50
PhyloP100		-0.66
PromoterAI		0.049	Neutral
Mutation Taster		=100/0	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: rs544136842; hg19: chr15-44955786;