5-40964714-C-A

Variant names:

• chr5-40964714-C-A
• rs7713884
• NM_000587.4:c.1750-27C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000587.4(C7):​c.1750-27C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,599,236 control chromosomes in the GnomAD database, including 46,542 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.27 (5590 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40952 hom.)
• Consequence: C7 NM_000587.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0620
• Publications: 7 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: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C7	NM_000587.4	c.1750-27C>A		intron_variant	Intron 13 of 17	ENST00000313164.10	NP_000578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C7	ENST00000313164.10	c.1750-27C>A		intron_variant	Intron 13 of 17	1	NM_000587.4	ENSP00000322061.9

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40272 AN: 151870 Hom.: 5588 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.263

GnomAD2 exomes AF: 0.250 AC: 61274 AN: 245016 AF XY: 0.256

Gnomad AFR exome AF: 0.346

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.281

Gnomad EAS exome AF: 0.349

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.229

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.233 AC: 336539 AN: 1447248 Hom.: 40952 Cov.: 28 AF XY: 0.236 AC XY: 170046 AN XY: 720216

African (AFR) AF: 0.349 AC: 11526 AN: 33026

American (AMR) AF: 0.163 AC: 7165 AN: 43848

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7265 AN: 25956

East Asian (EAS) AF: 0.293 AC: 11581 AN: 39546

South Asian (SAS) AF: 0.320 AC: 27106 AN: 84608

European-Finnish (FIN) AF: 0.231 AC: 12328 AN: 53330

Middle Eastern (MID) AF: 0.315 AC: 1806 AN: 5732

European-Non Finnish (NFE) AF: 0.220 AC: 242304 AN: 1101316

Other (OTH) AF: 0.258 AC: 15458 AN: 59886

GnomAD4 genome AF: 0.265 AC: 40304 AN: 151988 Hom.: 5590 Cov.: 32 AF XY: 0.269 AC XY: 19942 AN XY: 74272

African (AFR) AF: 0.345 AC: 14288 AN: 41448

American (AMR) AF: 0.190 AC: 2903 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 997 AN: 3470

East Asian (EAS) AF: 0.335 AC: 1729 AN: 5164

South Asian (SAS) AF: 0.340 AC: 1638 AN: 4818

European-Finnish (FIN) AF: 0.235 AC: 2476 AN: 10542

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15397 AN: 67964

Other (OTH) AF: 0.268 AC: 565 AN: 2106

Alfa AF: 0.252 Hom.: 908

Bravo AF: 0.262

Asia WGS AF: 0.339 AC: 1178 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.8
DANN	Benign	0.59
PhyloP100		0.062
BranchPoint Hunter		3.0
Mutation Taster		=100/0	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: rs7713884; hg19: chr5-40964816; COSMIC: COSV57480693; COSMIC: COSV57480693;