chr5-40964750-A-C

Variant names:

• chr5-40964750-A-C
• rs13157656
• NM_000587.4:c.1759A>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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. T587K) has been classified as Uncertain significance.

• 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
• Publications: 37 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1169276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.357 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.1759A>C	p.Thr587Pro	missense	Exon 14 of 18	NP_000578.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C7	ENST00000313164.10	TSL:1 MANE Select	c.1759A>C	p.Thr587Pro	missense	Exon 14 of 18	ENSP00000322061.9	P10643
	C7	ENST00000908410.1		c.1903A>C	p.Thr635Pro	missense	Exon 15 of 19	ENSP00000578469.1
	C7	ENST00000908412.1		c.1849A>C	p.Thr617Pro	missense	Exon 15 of 19	ENSP00000578471.1

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

GnomAD2 exomes AF: 0.240 AC: 59740 AN: 248552 AF XY: 0.250

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 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

African (AFR) AF: 0.0549 AC: 1836 AN: 33448

American (AMR) AF: 0.218 AC: 9732 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 6384 AN: 26118

East Asian (EAS) AF: 0.241 AC: 9560 AN: 39666

South Asian (SAS) AF: 0.374 AC: 32212 AN: 86086

European-Finnish (FIN) AF: 0.232 AC: 12408 AN: 53396

Middle Eastern (MID) AF: 0.232 AC: 1335 AN: 5754

European-Non Finnish (NFE) AF: 0.235 AC: 261198 AN: 1110280

Other (OTH) AF: 0.237 AC: 14314 AN: 60300

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

African (AFR) AF: 0.0622 AC: 2585 AN: 41546

American (AMR) AF: 0.228 AC: 3486 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 830 AN: 3472

East Asian (EAS) AF: 0.242 AC: 1251 AN: 5172

South Asian (SAS) AF: 0.371 AC: 1790 AN: 4826

European-Finnish (FIN) AF: 0.247 AC: 2610 AN: 10582

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.241 AC: 16413 AN: 67994

Other (OTH) AF: 0.198 AC: 418 AN: 2116

Alfa AF: 0.222 Hom.: 12188

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-1.3
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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