rs1063499

Positions:

• chr5-40955459-G-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.1166G>C​(p.Ser389Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.58 in 1,612,408 control chromosomes in the GnomAD database, including 274,957 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.52 (21765 hom., cov: 32)
  • Exomes 𝑓: 0.59 (253192 hom.)
• Consequence: C7 NM_000587.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.42

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=3.067753E-5).
• BP6: Variant 5-40955459-G-C is Benign according to our data. Variant chr5-40955459-G-C is described in ClinVar as [Benign]. Clinvar id is 1169275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-40955459-G-C is described in Lovd as [Benign]. Variant chr5-40955459-G-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C7	NM_000587.4	c.1166G>C	p.Ser389Thr	missense_variant	10/18	ENST00000313164.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C7	ENST00000313164.10	c.1166G>C	p.Ser389Thr	missense_variant	10/18	1	NM_000587.4	P1

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79420 AN: 151914 Hom.: 21760 Cov.: 32

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.659

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.551

GnomAD3 exomes AF: 0.575 AC: 142760 AN: 248154 Hom.: 41803 AF XY: 0.579 AC XY: 77926 AN XY: 134646

Gnomad AFR exome AF: 0.320

Gnomad AMR exome AF: 0.584

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.569

Gnomad SAS exome AF: 0.536

Gnomad FIN exome AF: 0.640

Gnomad NFE exome AF: 0.598

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.586 AC: 856107 AN: 1460376 Hom.: 253192 Cov.: 40 AF XY: 0.586 AC XY: 425484 AN XY: 726488

Gnomad4 AFR exome AF: 0.322

Gnomad4 AMR exome AF: 0.580

Gnomad4 ASJ exome AF: 0.658

Gnomad4 EAS exome AF: 0.505

Gnomad4 SAS exome AF: 0.536

Gnomad4 FIN exome AF: 0.645

Gnomad4 NFE exome AF: 0.597

Gnomad4 OTH exome AF: 0.579

GnomAD4 genome AF: 0.523 AC: 79457 AN: 152032 Hom.: 21765 Cov.: 32 AF XY: 0.527 AC XY: 39193 AN XY: 74324

Gnomad4 AFR AF: 0.333

Gnomad4 AMR AF: 0.569

Gnomad4 ASJ AF: 0.659

Gnomad4 EAS AF: 0.539

Gnomad4 SAS AF: 0.537

Gnomad4 FIN AF: 0.659

Gnomad4 NFE AF: 0.596

Gnomad4 OTH AF: 0.554

Alfa AF: 0.590 Hom.: 20094

Bravo AF: 0.507

TwinsUK AF: 0.581 AC: 2156

ALSPAC AF: 0.587 AC: 2263

ESP6500AA AF: 0.345 AC: 1310

ESP6500EA AF: 0.613 AC: 5060

ExAC AF: 0.570 AC: 68817

Asia WGS AF: 0.511 AC: 1777 AN: 3476

EpiCase AF: 0.601

EpiControl AF: 0.603

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	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2019	- -

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	0.13
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T
Eigen	Benign	0.043
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.000031	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.17
Sift	Benign	0.067	T
Sift4G	Uncertain	0.013	D
Polyphen		0.94	P
Vest4		0.19
MPC		0.061
ClinPred		0.037	T
GERP RS		1.4
Varity_R		0.28
gMVP		0.60

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: rs1063499; hg19: chr5-40955561; COSMIC: COSV57475104;