Genetic Variant C7:p.Phe7Leu (chr5-40928594-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000587.4(C7):c.21C>A(p.Phe7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000013 in 1,544,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

C7
NM_000587.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.934

Publications

0 publications found

Variant links:

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)

C7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09235078).

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.21C>A	p.Phe7Leu	missense	Exon 2 of 18	NP_000578.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C7	ENST00000313164.10	TSL:1 MANE Select	c.21C>A	p.Phe7Leu	missense	Exon 2 of 18	ENSP00000322061.9	P10643
C7	ENST00000908410.1		c.21C>A	p.Phe7Leu	missense	Exon 2 of 19	ENSP00000578469.1
C7	ENST00000908412.1		c.21C>A	p.Phe7Leu	missense	Exon 2 of 19	ENSP00000578471.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000115

AC:

AN:

173564

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000995

Gnomad AMR exome

AF:

0.0000386

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.18e-7

AC:

AN:

1391896

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688204

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31710

American (AMR)

AF:

0.0000272

AC:

AN:

36698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25162

East Asian (EAS)

AF:

0.00

AC:

AN:

36820

South Asian (SAS)

AF:

0.00

AC:

AN:

77440

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1070468

Other (OTH)

AF:

0.00

AC:

AN:

57812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41538

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.023

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.52

M_CAP

Benign

0.012

MetaRNN

Benign

0.092

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.58

PhyloP100

0.93

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.18

REVEL

Benign

0.055

Sift

Benign

0.92

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.27

MutPred

0.30

Gain of disorder (P = 0.0955)

MVP

0.23

MPC

0.018

ClinPred

0.018

GERP RS

2.5

Varity_R

0.047

gMVP

0.18

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over