1-25390874-C-G

Variant names:

• chr1-25390874-C-G
• rs609320
• NM_020485.8:c.676G>C

Variant summary

Our verdict is Benign. The variant received -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. 12/19 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
• Publications: 36 publications found

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]

RHCE Gene-Disease associations (from GenCC):

• Rh deficiency syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
RHCE	NM_020485.8	c.676G>C	p.Ala226Pro	missense_variant	Exon 5 of 10	ENST00000294413.13	NP_065231.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHCE	ENST00000294413.13	c.676G>C	p.Ala226Pro	missense_variant	Exon 5 of 10	1	NM_020485.8	ENSP00000294413.6

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

GnomAD2 exomes AF: 0.169 AC: 42500 AN: 251470 AF XY: 0.163

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 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

African (AFR) AF: 0.0987 AC: 3303 AN: 33474

American (AMR) AF: 0.257 AC: 11488 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3591 AN: 26136

East Asian (EAS) AF: 0.273 AC: 10827 AN: 39698

South Asian (SAS) AF: 0.107 AC: 9237 AN: 86256

European-Finnish (FIN) AF: 0.194 AC: 10369 AN: 53420

Middle Eastern (MID) AF: 0.146 AC: 845 AN: 5768

European-Non Finnish (NFE) AF: 0.156 AC: 173116 AN: 1111992

Other (OTH) AF: 0.152 AC: 9193 AN: 60388

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

African (AFR) AF: 0.105 AC: 4374 AN: 41546

American (AMR) AF: 0.222 AC: 3402 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 461 AN: 3470

East Asian (EAS) AF: 0.241 AC: 1245 AN: 5160

South Asian (SAS) AF: 0.102 AC: 490 AN: 4820

European-Finnish (FIN) AF: 0.182 AC: 1924 AN: 10590

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10451 AN: 68000

Other (OTH) AF: 0.145 AC: 306 AN: 2114

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
PhyloP100		0.74
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs609320; hg19: chr1-25717365; COSMIC: COSV53799790;