5-40931135-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000587.4(C7):c.134C>T(p.Thr45Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000518 in 1,611,540 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00086 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (6 hom.)
• Consequence: C7 NM_000587.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.12

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010451585).
• BP6: Variant 5-40931135-C-T is Benign according to our data. Variant chr5-40931135-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1084122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C7	NM_000587.4	c.134C>T	p.Thr45Ile	missense_variant	3/18	ENST00000313164.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C7	ENST00000313164.10	c.134C>T	p.Thr45Ile	missense_variant	3/18	1	NM_000587.4	P1

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000961 AC: 239 AN: 248634 Hom.: 4 AF XY: 0.000801 AC XY: 108 AN XY: 134862

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00111

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000482 AC: 703 AN: 1459266 Hom.: 6 Cov.: 29 AF XY: 0.000443 AC XY: 322 AN XY: 726070

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00602

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00255

Gnomad4 SAS exome AF: 0.000476

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000223

Gnomad4 OTH exome AF: 0.000597

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74472

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000247 Hom.: 0

Bravo AF: 0.00124

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000267 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000522 AC: 63

Asia WGS AF: 0.00173 AC: 6 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

C7-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.19
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.33
MVP		0.76
MPC		0.036
ClinPred		0.047	T
GERP RS		5.5
Varity_R		0.48
gMVP		0.33

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: rs78327832; hg19: chr5-40931237; COSMIC: COSV57470921; COSMIC: COSV57470921;