1-25390874-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020485.8(RHCE):c.676G>C(p.Ala226Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,614,060 control chromosomes in the GnomAD database, including 21,239 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (1844 hom., cov: 31)
  • Exomes 𝑓: 0.16 (19395 hom.)
• Consequence: RHCE NM_020485.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.742

Genes affected

RHCE (HGNC:10008): (Rh blood group CcEe antigens) The Rh blood group system is the second most clinically significant of the blood groups, second only to ABO. It is also the most polymorphic of the blood groups, with variations due to deletions, gene conversions, and missense mutations. The Rh blood group includes this gene which encodes both the RhC and RhE antigens on a single polypeptide and a second gene which encodes the RhD protein. The classification of Rh-positive and Rh-negative individuals is determined by the presence or absence of the highly immunogenic RhD protein on the surface of erythrocytes. A mutation in this gene results in amorph-type Rh-null disease. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005598724).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHCE	NM_020485.8	c.676G>C	p.Ala226Pro	missense_variant	5/10	ENST00000294413.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHCE	ENST00000294413.13	c.676G>C	p.Ala226Pro	missense_variant	5/10	1	NM_020485.8	P1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22727 AN: 152086 Hom.: 1843 Cov.: 31

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.145

GnomAD3 exomes AF: 0.169 AC: 42500 AN: 251470 Hom.: 4026 AF XY: 0.163 AC XY: 22102 AN XY: 135904

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.259

Gnomad ASJ exome AF: 0.136

Gnomad EAS exome AF: 0.242

Gnomad SAS exome AF: 0.106

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.159 AC: 231969 AN: 1461856 Hom.: 19395 Cov.: 34 AF XY: 0.157 AC XY: 113932 AN XY: 727228

Gnomad4 AFR exome AF: 0.0987

Gnomad4 AMR exome AF: 0.257

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.273

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.194

Gnomad4 NFE exome AF: 0.156

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.149 AC: 22734 AN: 152204 Hom.: 1844 Cov.: 31 AF XY: 0.151 AC XY: 11241 AN XY: 74402

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.241

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.182

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.145

Alfa AF: 0.128 Hom.: 463

Bravo AF: 0.152

TwinsUK AF: 0.158 AC: 586

ALSPAC AF: 0.160 AC: 616

ESP6500AA AF: 0.115 AC: 508

ESP6500EA AF: 0.154 AC: 1324

ExAC AF: 0.162 AC: 19691

Asia WGS AF: 0.173 AC: 601 AN: 3478

EpiCase AF: 0.148

EpiControl AF: 0.141

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	13
Dann	Uncertain	1.0
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.70	T;T;T;T
MetaRNN	Benign	0.0056	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.27	P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Benign	0.11
Sift	Benign	0.066	T;T;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.026	.;.;B;.
Vest4		0.32
MPC		0.39
ClinPred		0.018	T
GERP RS		3.1
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs609320; hg19: chr1-25717365; COSMIC: COSV53799790;