1-25420739-G-C

Variant names:

• chr1-25420739-G-C
• rs586178
• NM_020485.8:c.48C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_020485.8(RHCE):​c.48C>G​(p.Cys16Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,198,092 control chromosomes in the GnomAD database, including 219,438 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency:
  • Genomes: 𝑓 0.50 (19224 hom., cov: 26)
  • Exomes 𝑓: 0.50 (200214 hom.)
• Consequence: RHCE NM_020485.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.607
• Publications: 41 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.82844E-4).
• BS2: High Homozygotes in GnomAd4 at 19224 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020485.8. 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
	RHCE	NM_020485.8	MANE Select	c.48C>G	p.Cys16Trp	missense	Exon 1 of 10	NP_065231.4	P18577-1
	RHCE	NM_001330430.4		c.48C>G	p.Cys16Trp	missense	Exon 1 of 9	NP_001317359.1
	RHCE	NM_138618.6		c.48C>G	p.Cys16Trp	missense	Exon 1 of 9	NP_619524.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHCE	ENST00000294413.13	TSL:1 MANE Select	c.48C>G	p.Cys16Trp	missense	Exon 1 of 10	ENSP00000294413.6	P18577-1
	RHCE	ENST00000413854.5	TSL:1	c.48C>G	p.Cys16Trp	missense	Exon 1 of 9	ENSP00000415417.2	E7EU00
	RHCE	ENST00000349438.8	TSL:1	c.48C>G	p.Cys16Trp	missense	Exon 1 of 9	ENSP00000334570.5	P18577-2

Frequencies

GnomAD3 genomes AF: 0.503 AC: 74691 AN: 148566 Hom.: 19200 Cov.: 26

Gnomad AFR AF: 0.498

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.485

GnomAD2 exomes AF: 0.413 AC: 73315 AN: 177690 AF XY: 0.408

Gnomad AFR exome AF: 0.419

Gnomad AMR exome AF: 0.372

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.218

Gnomad FIN exome AF: 0.506

Gnomad NFE exome AF: 0.491

Gnomad OTH exome AF: 0.459

GnomAD4 exome AF: 0.498 AC: 522380 AN: 1049406 Hom.: 200214 Cov.: 43 AF XY: 0.489 AC XY: 258004 AN XY: 527688

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

African (AFR) AF: 0.480 AC: 12001 AN: 24990

American (AMR) AF: 0.388 AC: 13377 AN: 34482

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 8978 AN: 21362

East Asian (EAS) AF: 0.287 AC: 10570 AN: 36806

South Asian (SAS) AF: 0.299 AC: 21746 AN: 72640

European-Finnish (FIN) AF: 0.534 AC: 23943 AN: 44822

Middle Eastern (MID) AF: 0.419 AC: 1844 AN: 4400

European-Non Finnish (NFE) AF: 0.535 AC: 408196 AN: 763264

Other (OTH) AF: 0.466 AC: 21725 AN: 46640

⚠️ 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 AF: 0.503 AC: 74752 AN: 148686 Hom.: 19224 Cov.: 26 AF XY: 0.497 AC XY: 35973 AN XY: 72450

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

African (AFR) AF: 0.498 AC: 20170 AN: 40466

American (AMR) AF: 0.489 AC: 7317 AN: 14950

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1575 AN: 3420

East Asian (EAS) AF: 0.267 AC: 1348 AN: 5046

South Asian (SAS) AF: 0.317 AC: 1494 AN: 4720

European-Finnish (FIN) AF: 0.527 AC: 5360 AN: 10164

Middle Eastern (MID) AF: 0.490 AC: 141 AN: 288

European-Non Finnish (NFE) AF: 0.538 AC: 35912 AN: 66702

Other (OTH) AF: 0.480 AC: 981 AN: 2042

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.404 Hom.: 1803

Bravo AF: 0.504

ExAC AF: 0.405 AC: 48959

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.8
DANN	Benign	0.63
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.00058	T
MetaSVM	Benign	-0.90	T
PhyloP100		-0.61
PrimateAI	Benign	0.47	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.032
Sift	Benign	1.0	T
Sift4G	Benign	0.37	T
Polyphen		0.0010	B
Vest4		0.12
MPC		2.2
ClinPred		0.0069	T
GERP RS		0.63
PromoterAI		0.046	Neutral
gMVP		0.59
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs586178; hg19: chr1-25747230; COSMIC: COSV53798298;