Genetic Variant NM_003119.4:c.1032C>T (chr16-89531948-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_003119.4(SPG7):c.1032C>T(p.Gly344Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,614,118 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0045 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 51 hom. )

Consequence

SPG7
NM_003119.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -1.58

Publications

3 publications found

Variant links:

Genes affected

SPG7 (HGNC:11237): (SPG7 matrix AAA peptidase subunit, paraplegin) This gene encodes a mitochondrial metalloprotease protein that is a member of the AAA family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. Mutations in this gene cause autosomal recessive spastic paraplegia 7. Two transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Mar 2014]

SPG7 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 7
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
autosomal dominant optic atrophy
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPG7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 16-89531948-C-T is Benign according to our data. Variant chr16-89531948-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 139239.

BP7

Synonymous conserved (PhyloP=-1.58 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00453 (690/152352) while in subpopulation NFE AF = 0.00725 (493/68026). AF 95% confidence interval is 0.00672. There are 5 homozygotes in GnomAd4. There are 299 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003119.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG7	NM_003119.4	MANE Select	c.1032C>T	p.Gly344Gly	synonymous	Exon 8 of 17	NP_003110.1	Q9UQ90-1
SPG7	NM_001363850.1		c.1032C>T	p.Gly344Gly	synonymous	Exon 8 of 18	NP_001350779.1	A0A2R8Y3M4
SPG7	NM_199367.3		c.1032C>T	p.Gly344Gly	synonymous	Exon 8 of 10	NP_955399.1	Q9UQ90-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG7	ENST00000645818.2	MANE Select	c.1032C>T	p.Gly344Gly	synonymous	Exon 8 of 17	ENSP00000495795.2	Q9UQ90-1
SPG7	ENST00000268704.7	TSL:1	c.1011C>T	p.Gly337Gly	synonymous	Exon 8 of 17	ENSP00000268704.3	A0A2U3TZH1
SPG7	ENST00000341316.6	TSL:1	c.1032C>T	p.Gly344Gly	synonymous	Exon 8 of 10	ENSP00000341157.2	Q9UQ90-2

Frequencies

GnomAD3 genomes

AF:

0.00455

AC:

693

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.00379

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00725

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00494

AC:

1240

AN:

250820

AF XY:

0.00531

show subpopulations

Gnomad AFR exome

AF:

0.000617

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000694

Gnomad NFE exome

AF:

0.00775

Gnomad OTH exome

AF:

0.00605

GnomAD4 exome

AF:

0.00591

AC:

8645

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00606

AC XY:

4410

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.000956

AC:

AN:

33476

American (AMR)

AF:

0.00266

AC:

119

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00356

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.00627

AC:

541

AN:

86256

European-Finnish (FIN)

AF:

0.000768

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.0208

AC:

120

AN:

5764

European-Non Finnish (NFE)

AF:

0.00656

AC:

7293

AN:

1111938

Other (OTH)

AF:

0.00671

AC:

405

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

505

1011

1516

2022

2527

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

252

504

756

1008

1260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00453

AC:

690

AN:

152352

Hom.:

Cov.:

AF XY:

0.00401

AC XY:

299

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000842

AC:

AN:

41590

American (AMR)

AF:

0.00379

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00435

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00725

AC:

493

AN:

68026

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

116

154

193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00610

Hom.:

Bravo

AF:

0.00491

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00796

EpiControl

AF:

0.00871

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 7 (2)

not specified (2)

Hereditary spastic paraplegia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.67

(source)

DANN

Benign

0.89

PhyloP100

-1.6

PromoterAI

-0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over