rs74590011

Variant names:

• chr16-89553778-C-G
• rs74590011
• NM_003119.4:c.1937-16C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-89553778-C-G
• chr16-89553778-C-T
• chr16-89553778-C-A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_003119.4(SPG7):​c.1937-16C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,613,098 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (21 hom.)
• Consequence: SPG7 NM_003119.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0670
• Publications: 2 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: 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 16-89553778-C-G is Benign according to our data. Variant chr16-89553778-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0059 (899/152312) while in subpopulation AFR AF = 0.0161 (670/41564). AF 95% confidence interval is 0.0151. There are 3 homozygotes in GnomAd4. There are 441 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1937-16C>G		intron	N/A	NP_003110.1	Q9UQ90-1
	SPG7	NM_001363850.1		c.1937-16C>G		intron	N/A	NP_001350779.1	A0A2R8Y3M4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.1937-16C>G		intron	N/A	ENSP00000495795.2	Q9UQ90-1
	SPG7	ENST00000268704.7	TSL:1	c.1916-16C>G		intron	N/A	ENSP00000268704.3	A0A2U3TZH1
	SPG7	ENST00000965632.1		c.1957C>G	p.Arg653Gly	missense	Exon 15 of 17	ENSP00000635691.1

Frequencies

GnomAD3 genomes AF: 0.00585 AC: 890 AN: 152194 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00328 AC: 819 AN: 249890 AF XY: 0.00297

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00228 AC: 3331 AN: 1460786 Hom.: 21 Cov.: 32 AF XY: 0.00224 AC XY: 1629 AN XY: 726722

African (AFR) AF: 0.0188 AC: 630 AN: 33464

American (AMR) AF: 0.00411 AC: 184 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26130

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

South Asian (SAS) AF: 0.00209 AC: 180 AN: 86250

European-Finnish (FIN) AF: 0.000419 AC: 22 AN: 52550

Middle Eastern (MID) AF: 0.0284 AC: 164 AN: 5766

European-Non Finnish (NFE) AF: 0.00167 AC: 1860 AN: 1111828

Other (OTH) AF: 0.00411 AC: 248 AN: 60374

GnomAD4 genome AF: 0.00590 AC: 899 AN: 152312 Hom.: 3 Cov.: 33 AF XY: 0.00592 AC XY: 441 AN XY: 74474

African (AFR) AF: 0.0161 AC: 670 AN: 41564

American (AMR) AF: 0.00340 AC: 52 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4820

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00213 AC: 145 AN: 68028

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00310 Hom.: 1

Bravo AF: 0.00702

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_noAF	Benign	-0.91
CADD	Benign	11
DANN	Benign	0.60
PhyloP100		-0.067
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: -20

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

Other links and lift over

dbSNP: rs74590011; hg19: chr16-89620186; COSMIC: COSV51953139; COSMIC: COSV51953139;