16-89549357-T-G

Variant names:

• chr16-89549357-T-G
• rs2019604
• NM_003119.4:c.1664-1137T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003119.4(SPG7):​c.1664-1137T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 390,954 control chromosomes in the GnomAD database, including 4,049 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1307 hom., cov: 33)
  • Exomes 𝑓: 0.14 (2742 hom.)
• Consequence: SPG7 NM_003119.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0270
• Publications: 23 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	NM_003119.4	MANE Select	c.1664-1137T>G		intron	N/A	NP_003110.1
	SPG7	NM_001363850.1		c.1664-1137T>G		intron	N/A	NP_001350779.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.1664-1137T>G		intron	N/A	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.1643-1137T>G		intron	N/A	ENSP00000268704.3
	SPG7	ENST00000561702.6	TSL:2	n.1199T>G		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18209 AN: 152132 Hom.: 1303 Cov.: 33

Gnomad AFR AF: 0.0566

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0651

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.152

GnomAD2 exomes AF: 0.139 AC: 11984 AN: 86048 AF XY: 0.144

Gnomad AFR exome AF: 0.0510

Gnomad AMR exome AF: 0.0952

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.148

Gnomad FIN exome AF: 0.0805

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.145 AC: 34538 AN: 238704 Hom.: 2742 Cov.: 0 AF XY: 0.145 AC XY: 19377 AN XY: 133352

African (AFR) AF: 0.0543 AC: 350 AN: 6440

American (AMR) AF: 0.0897 AC: 1611 AN: 17962

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 1357 AN: 6530

East Asian (EAS) AF: 0.141 AC: 1218 AN: 8632

South Asian (SAS) AF: 0.142 AC: 6814 AN: 48042

European-Finnish (FIN) AF: 0.0811 AC: 842 AN: 10388

Middle Eastern (MID) AF: 0.137 AC: 334 AN: 2442

European-Non Finnish (NFE) AF: 0.160 AC: 20294 AN: 126814

Other (OTH) AF: 0.150 AC: 1718 AN: 11454

GnomAD4 genome AF: 0.120 AC: 18222 AN: 152250 Hom.: 1307 Cov.: 33 AF XY: 0.115 AC XY: 8573 AN XY: 74458

African (AFR) AF: 0.0569 AC: 2364 AN: 41536

American (AMR) AF: 0.113 AC: 1729 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 784 AN: 3470

East Asian (EAS) AF: 0.146 AC: 758 AN: 5178

South Asian (SAS) AF: 0.142 AC: 684 AN: 4822

European-Finnish (FIN) AF: 0.0651 AC: 691 AN: 10610

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10565 AN: 68016

Other (OTH) AF: 0.153 AC: 323 AN: 2112

Alfa AF: 0.141 Hom.: 3300

Bravo AF: 0.120

Asia WGS AF: 0.110 AC: 381 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.5
DANN	Benign	0.80
PhyloP100		0.027
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: rs2019604; hg19: chr16-89615765; COSMIC: COSV51950225; COSMIC: COSV51950225;