NM_000562.3:c.1454G>T

Variant names:

• chr1-56912476-G-T
• rs1620075
• NM_000562.3:c.1454G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000562.3(C8A):​c.1454G>T​(p.Arg485Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.062 in 1,614,080 control chromosomes in the GnomAD database, including 4,764 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R485H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.10 (1238 hom., cov: 33)
  • Exomes 𝑓: 0.058 (3526 hom.)
• Consequence: C8A NM_000562.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047442913).
• BP6: Variant 1-56912476-G-T is Benign according to our data. Variant chr1-56912476-G-T is described in ClinVar as [Benign]. Clinvar id is 402461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C8A	NM_000562.3	c.1454G>T	p.Arg485Leu	missense_variant	Exon 10 of 11	ENST00000361249.4	NP_000553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C8A	ENST00000361249.4	c.1454G>T	p.Arg485Leu	missense_variant	Exon 10 of 11	1	NM_000562.3	ENSP00000354458.3

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15558 AN: 152120 Hom.: 1236 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.0519

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0470

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.104

GnomAD3 exomes AF: 0.0755 AC: 18985 AN: 251300 Hom.: 1071 AF XY: 0.0751 AC XY: 10209 AN XY: 135868

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.0917

Gnomad ASJ exome AF: 0.0454

Gnomad EAS exome AF: 0.0518

Gnomad SAS exome AF: 0.134

Gnomad FIN exome AF: 0.0483

Gnomad NFE exome AF: 0.0454

Gnomad OTH exome AF: 0.0711

GnomAD4 exome AF: 0.0578 AC: 84527 AN: 1461842 Hom.: 3526 Cov.: 33 AF XY: 0.0596 AC XY: 43315 AN XY: 727228

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.0928

Gnomad4 ASJ exome AF: 0.0430

Gnomad4 EAS exome AF: 0.0651

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.0459

Gnomad4 NFE exome AF: 0.0454

Gnomad4 OTH exome AF: 0.0678

GnomAD4 genome AF: 0.102 AC: 15580 AN: 152238 Hom.: 1238 Cov.: 33 AF XY: 0.102 AC XY: 7590 AN XY: 74440

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.0415

Gnomad4 EAS AF: 0.0518

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.0470

Gnomad4 NFE AF: 0.0456

Gnomad4 OTH AF: 0.102

Alfa AF: 0.0350 Hom.: 32

Bravo AF: 0.110

TwinsUK AF: 0.0467 AC: 173

ALSPAC AF: 0.0418 AC: 161

ESP6500AA AF: 0.196 AC: 864

ESP6500EA AF: 0.0430 AC: 370

ExAC AF: 0.0774 AC: 9394

EpiCase AF: 0.0478

EpiControl AF: 0.0510

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	2.9	M
PrimateAI	Benign	0.20	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.10	T
Polyphen		0.86	P
Vest4		0.11
MPC		0.043
ClinPred		0.088	T
GERP RS		0.70
Varity_R		0.66
gMVP		0.78

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: COSV63484437;