rs1391593801

Variant names:

• chr5-40928576-C-A
• rs1391593801
• NM_000587.4:c.7-4C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-40928576-C-A
• chr5-40928576-C-G
• chr5-40928576-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000587.4(C7):​c.7-4C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,345,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: C7 NM_000587.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002397
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.330
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.7-4C>A		splice_region intron	N/A	NP_000578.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C7	ENST00000313164.10	TSL:1 MANE Select	c.7-4C>A		splice_region intron	N/A	ENSP00000322061.9	P10643
	C7	ENST00000908410.1		c.7-4C>A		splice_region intron	N/A	ENSP00000578469.1
	C7	ENST00000908412.1		c.7-4C>A		splice_region intron	N/A	ENSP00000578471.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1345024 Hom.: 0 Cov.: 24 AF XY: 0.00000150 AC XY: 1 AN XY: 665880

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30178

American (AMR) AF: 0.00 AC: 0 AN: 33120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24784

East Asian (EAS) AF: 0.00 AC: 0 AN: 35788

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1036508

Other (OTH) AF: 0.00 AC: 0 AN: 56186

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.82
DANN	Benign	0.51
PhyloP100		-0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0
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: rs1391593801; hg19: chr5-40928678;