rs1063499

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S389I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.52 ( 21765 hom., cov: 32)

Exomes 𝑓: 0.59 ( 253192 hom. )

Consequence

C7
NM_000587.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.42

Publications

41 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: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)

C7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 1169275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

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.1166G>C	p.Ser389Thr	missense	Exon 10 of 18	NP_000578.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
C7	ENST00000313164.10	TSL:1 MANE Select	c.1166G>C	p.Ser389Thr	missense	Exon 10 of 18	ENSP00000322061.9
C7	ENST00000908410.1		c.1166G>C	p.Ser389Thr	missense	Exon 10 of 19	ENSP00000578469.1
C7	ENST00000908412.1		c.1166G>C	p.Ser389Thr	missense	Exon 10 of 19	ENSP00000578471.1

Frequencies

GnomAD3 genomes

AF:

0.523

AC:

79420

AN:

151914

Hom.:

21760

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.575

AC:

142760

AN:

248154

AF XY:

0.579

show subpopulations

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 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.:

AF XY:

0.586

AC XY:

425484

AN XY:

726488

show subpopulations

African (AFR)

AF:

0.322

AC:

10774

AN:

33430

American (AMR)

AF:

0.580

AC:

25850

AN:

44538

Ashkenazi Jewish (ASJ)

AF:

0.658

AC:

17174

AN:

26114

East Asian (EAS)

AF:

0.505

AC:

20031

AN:

39638

South Asian (SAS)

AF:

0.536

AC:

46110

AN:

86008

European-Finnish (FIN)

AF:

0.645

AC:

34427

AN:

53384

Middle Eastern (MID)

AF:

0.614

AC:

3537

AN:

5764

European-Non Finnish (NFE)

AF:

0.597

AC:

663262

AN:

1111166

Other (OTH)

AF:

0.579

AC:

34942

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

17869

35738

53606

71475

89344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18014

36028

54042

72056

90070

<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:

0.523

AC:

79457

AN:

152032

Hom.:

21765

Cov.:

AF XY:

0.527

AC XY:

39193

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.333

AC:

13815

AN:

41458

American (AMR)

AF:

0.569

AC:

8681

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.659

AC:

2289

AN:

3472

East Asian (EAS)

AF:

0.539

AC:

2784

AN:

5166

South Asian (SAS)

AF:

0.537

AC:

2586

AN:

4814

European-Finnish (FIN)

AF:

0.659

AC:

6964

AN:

10564

Middle Eastern (MID)

AF:

0.636

AC:

187

AN:

294

European-Non Finnish (NFE)

AF:

0.596

AC:

40523

AN:

67978

Other (OTH)

AF:

0.554

AC:

1168

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1890

3780

5671

7561

9451

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

696

1392

2088

2784

3480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

Eigen

Benign

0.043

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.44

MetaRNN

Benign

0.000031

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.8

PhyloP100

1.4

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.9

REVEL

Benign

0.17

Sift

Benign

0.067

Sift4G

Uncertain

0.013

Polyphen

0.94

Vest4

0.19

MPC

0.061

ClinPred

0.037

GERP RS

1.4

Varity_R

0.28

gMVP

0.60

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over