5-40964750-A-C

Position:

• chr5-40964750-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000587.4(C7):​c.1759A>C​(p.Thr587Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,611,870 control chromosomes in the GnomAD database, including 47,050 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (3476 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43574 hom.)
• Consequence: C7 NM_000587.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.26

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012661219).
• BP6: Variant 5-40964750-A-C is Benign according to our data. Variant chr5-40964750-A-C is described in ClinVar as [Benign]. Clinvar id is 1169276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-40964750-A-C is described in Lovd as [Benign]. Variant chr5-40964750-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C7	NM_000587.4	c.1759A>C	p.Thr587Pro	missense_variant	14/18	ENST00000313164.10	NP_000578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C7	ENST00000313164.10	c.1759A>C	p.Thr587Pro	missense_variant	14/18	1	NM_000587.4	ENSP00000322061	P1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29525 AN: 152074 Hom.: 3475 Cov.: 32

Gnomad AFR AF: 0.0623

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.197

GnomAD3 exomes AF: 0.240 AC: 59740 AN: 248552 Hom.: 7842 AF XY: 0.250 AC XY: 33752 AN XY: 134830

Gnomad AFR exome AF: 0.0575

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.240

Gnomad EAS exome AF: 0.228

Gnomad SAS exome AF: 0.375

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.241

GnomAD4 exome AF: 0.239 AC: 348979 AN: 1459678 Hom.: 43574 Cov.: 31 AF XY: 0.244 AC XY: 177151 AN XY: 726174

Gnomad4 AFR exome AF: 0.0549

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.241

Gnomad4 SAS exome AF: 0.374

Gnomad4 FIN exome AF: 0.232

Gnomad4 NFE exome AF: 0.235

Gnomad4 OTH exome AF: 0.237

GnomAD4 genome AF: 0.194 AC: 29543 AN: 152192 Hom.: 3476 Cov.: 32 AF XY: 0.199 AC XY: 14805 AN XY: 74400

Gnomad4 AFR AF: 0.0622

Gnomad4 AMR AF: 0.228

Gnomad4 ASJ AF: 0.239

Gnomad4 EAS AF: 0.242

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.247

Gnomad4 NFE AF: 0.241

Gnomad4 OTH AF: 0.198

Alfa AF: 0.230 Hom.: 8863

Bravo AF: 0.181

TwinsUK AF: 0.235 AC: 871

ALSPAC AF: 0.230 AC: 885

ESP6500AA AF: 0.0641 AC: 239

ESP6500EA AF: 0.235 AC: 1927

ExAC AF: 0.239 AC: 28863

Asia WGS AF: 0.314 AC: 1091 AN: 3478

EpiCase AF: 0.241

EpiControl AF: 0.236

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.2
DANN	Benign	0.74
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.61	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.048
Sift	Benign	0.15	T
Sift4G	Benign	0.28	T
Polyphen		0.0010	B
Vest4		0.035
MPC		0.018
ClinPred		0.00090	T
GERP RS		-4.7
Varity_R		0.46
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs13157656; hg19: chr5-40964852; COSMIC: COSV57474786; COSMIC: COSV57474786;