chr16-89556997-C-T

Variant names:

• chr16-89556997-C-T
• rs61747711
• NM_003119.4:c.2292C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003119.4(SPG7):​c.2292C>T​(p.Ile764Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0368 in 1,613,830 control chromosomes in the GnomAD database, including 1,277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (93 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1184 hom.)
• Consequence: SPG7 NM_003119.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.20
• Publications: 6 publications found

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: Laboratory for Molecular Medicine, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 16-89556997-C-T is Benign according to our data. Variant chr16-89556997-C-T is described in ClinVar as Benign. ClinVar VariationId is 139250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0281 (4274/152306) while in subpopulation NFE AF = 0.0409 (2781/68014). AF 95% confidence interval is 0.0396. There are 93 homozygotes in GnomAd4. There are 1970 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 93 AD,AR 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	NM_003119.4	MANE Select	c.2292C>T	p.Ile764Ile	synonymous	Exon 17 of 17	NP_003110.1
	SPG7	NM_001363850.1		c.*70C>T		3_prime_UTR	Exon 18 of 18	NP_001350779.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.2292C>T	p.Ile764Ile	synonymous	Exon 17 of 17	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.2271C>T	p.Ile757Ile	synonymous	Exon 17 of 17	ENSP00000268704.3
	SPG7	ENST00000918773.1		c.2382C>T	p.Ile794Ile	synonymous	Exon 17 of 17	ENSP00000588832.1

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4276 AN: 152188 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.0923

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0798

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0409

Gnomad OTH AF: 0.0406

GnomAD2 exomes AF: 0.0287 AC: 7212 AN: 251238 AF XY: 0.0292

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.0188

Gnomad ASJ exome AF: 0.0615

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0166

Gnomad NFE exome AF: 0.0436

Gnomad OTH exome AF: 0.0382

GnomAD4 exome AF: 0.0378 AC: 55173 AN: 1461524 Hom.: 1184 Cov.: 31 AF XY: 0.0368 AC XY: 26774 AN XY: 727048

African (AFR) AF: 0.00932 AC: 312 AN: 33474

American (AMR) AF: 0.0193 AC: 865 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 1688 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00883 AC: 762 AN: 86254

European-Finnish (FIN) AF: 0.0187 AC: 996 AN: 53260

Middle Eastern (MID) AF: 0.0322 AC: 183 AN: 5676

European-Non Finnish (NFE) AF: 0.0433 AC: 48137 AN: 1111934

Other (OTH) AF: 0.0369 AC: 2230 AN: 60370

GnomAD4 genome AF: 0.0281 AC: 4274 AN: 152306 Hom.: 93 Cov.: 32 AF XY: 0.0265 AC XY: 1970 AN XY: 74472

African (AFR) AF: 0.0110 AC: 457 AN: 41578

American (AMR) AF: 0.0239 AC: 366 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 277 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00974 AC: 47 AN: 4824

European-Finnish (FIN) AF: 0.0156 AC: 166 AN: 10624

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0409 AC: 2781 AN: 68014

Other (OTH) AF: 0.0402 AC: 85 AN: 2114

Alfa AF: 0.0374 Hom.: 338

Bravo AF: 0.0289

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0450

EpiControl AF: 0.0420

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 7 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.043
DANN	Benign	0.87
PhyloP100		-2.2
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: rs61747711; hg19: chr16-89623405;