chr5-40959520-C-G

Variant names:

• chr5-40959520-C-G
• rs121964920
• NM_000587.4:c.1561C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000587.4(C7):​c.1561C>G​(p.Arg521Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R521S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: C7 NM_000587.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.470
• Publications: 9 publications found

Genes affected

C7 (HGNC:1346): (complement C7) This gene encodes a serum glycoprotein that forms a membrane attack complex together with complement components C5b, C6, C8, and C9 as part of the terminal complement pathway of the innate immune system. The protein encoded by this gene contains a cholesterol-dependent cytolysin/membrane attack complex/perforin-like (CDC/MACPF) domain and belongs to a large family of structurally related molecules that form pores involved in host immunity and bacterial pathogenesis. This protein initiates membrane attack complex formation by binding the C5b-C6 subcomplex and inserts into the phospholipid bilayer, serving as a membrane anchor. Mutations in this gene are associated with a rare disorder called C7 deficiency. [provided by RefSeq, Nov 2016]

C7 Gene-Disease associations (from GenCC):

• complement component 7 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-40959520-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12105.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000587.4. 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
	C7	NM_000587.4	MANE Select	c.1561C>G	p.Arg521Gly	missense	Exon 12 of 18	NP_000578.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C7	ENST00000313164.10	TSL:1 MANE Select	c.1561C>G	p.Arg521Gly	missense	Exon 12 of 18	ENSP00000322061.9	P10643
	C7	ENST00000908410.1		c.1705C>G	p.Arg569Gly	missense	Exon 13 of 19	ENSP00000578469.1
	C7	ENST00000908412.1		c.1561C>G	p.Arg521Gly	missense	Exon 12 of 19	ENSP00000578471.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459326 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725796

African (AFR) AF: 0.0000299 AC: 1 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 85940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4778

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111294

Other (OTH) AF: 0.00 AC: 0 AN: 60226

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 5

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.22	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.018	T
MutationAssessor	Pathogenic	5.0	H
PhyloP100		0.47
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.88		Loss of MoRF binding (P = 0.0292)
MVP		0.78
MPC		0.15
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.99
gMVP		0.91
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121964920; hg19: chr5-40959622;