5-40955428-GGG-CGC

Variant names:

• chr5-40955428-GGG-CGC
• NM_000587.4:c.1135_1137delGGGinsCGC
• C7 p.Gly379Arg

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS1_Moderate PP3

The NM_000587.4(C7):​c.1135_1137delGGGinsCGC​(p.Gly379Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G379A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C7 NM_000587.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.86
• Publications: 0 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: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PS1: Transcript NM_000587.4 (C7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1135_1137delGGGinsCGC	p.Gly379Arg	missense	N/A	NP_000578.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C7	ENST00000313164.10	TSL:1 MANE Select	c.1135_1137delGGGinsCGC	p.Gly379Arg	missense	N/A	ENSP00000322061.9	P10643
	C7	ENST00000908410.1		c.1135_1137delGGGinsCGC	p.Gly379Arg	missense	N/A	ENSP00000578469.1
	C7	ENST00000908412.1		c.1135_1137delGGGinsCGC	p.Gly379Arg	missense	N/A	ENSP00000578471.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-40955530;