rs1620075

chr1-56912476-G-Achr1-56912476-G-Cchr1-56912476-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000562.3(C8A):c.1454G>A(p.Arg485His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,614,144 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R485L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (10 hom.)
• Consequence: C8A NM_000562.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.252

Genes affected

C8A (HGNC:1352): (complement C8 alpha chain) C8 is a component of the complement system and contains three polypeptides, alpha, beta and gamma. This gene encodes the alpha subunit of C8. C8 participates in the formation of the membrane attack complex (MAC). The MAC assembles on bacterial membranes to form a pore, permitting disruption of bacterial membrane organization. Mutations in this gene cause complement C8 alpha-gamma deficiency. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0131421685).
• BP6: Variant 1-56912476-G-A is Benign according to our data. Variant chr1-56912476-G-A is described in ClinVar as [Benign]. Clinvar id is 710241.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-56912476-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00129 (1883/1461884) while in subpopulation MID AF= 0.0257 (148/5768). AF 95% confidence interval is 0.0223. There are 10 homozygotes in gnomad4_exome. There are 1052 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C8A	NM_000562.3	c.1454G>A	p.Arg485His	missense_variant	10/11	ENST00000361249.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C8A	ENST00000361249.4	c.1454G>A	p.Arg485His	missense_variant	10/11	1	NM_000562.3	P4

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000532

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00195 AC: 491 AN: 251300 Hom.: 4 AF XY: 0.00216 AC XY: 293 AN XY: 135868

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00129 AC: 1883 AN: 1461884 Hom.: 10 Cov.: 33 AF XY: 0.00145 AC XY: 1052 AN XY: 727244

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00903

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00378

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000793

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.00117 AC XY: 87 AN XY: 74454

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00181 Hom.: 32

ExAC AF: 0.00183 AC: 222

EpiCase AF: 0.00300

EpiControl AF: 0.00261

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	11
Dann	Benign	0.96
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.0051	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.31
Sift	Benign	0.037	D
Sift4G	Uncertain	0.015	D
Polyphen		0.24	B
Vest4		0.18
MVP		0.79
MPC		0.042
ClinPred		0.084	T
GERP RS		0.70
Varity_R		0.56
gMVP		0.68

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

LitVar

Other links and lift over

dbSNP: rs1620075; hg19: chr1-57378149; COSMIC: COSV63485618;