dbSNP rs1053344: RHCE:p.Asn68Ser (chr1-25408815-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020485.8(RHCE):c.203A>G(p.Asn68Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.00016 ( 1 hom., cov: 20)

Exomes 𝑓: 0.000060 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

RHCE
NM_020485.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.01

Publications

5 publications found

Variant links:

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

RHCE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03341216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHCE	NM_020485.8 link	c.203A>G	p.Asn68Ser	missense_variant	Exon 2 of 10	ENST00000294413.13	NP_065231.4	P18577A0A220QMN8A0A1L3H056

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHCE	ENST00000294413.13 link	c.203A>G	p.Asn68Ser	missense_variant	Exon 2 of 10	1	NM_020485.8	ENSP00000294413.6		P18577

Frequencies

GnomAD3 genomes

AF:

0.000156

AC:

AN:

121430

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000901

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000150

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000370

AC:

AN:

189074

AF XY:

0.0000198

show subpopulations

Gnomad AFR exome

AF:

0.000251

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000327

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000603

AC:

AN:

1160314

Hom.:

Cov.:

AF XY:

0.0000577

AC XY:

AN XY:

571978

show subpopulations

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

African (AFR)

AF:

0.000121

AC:

AN:

32942

American (AMR)

AF:

0.00

AC:

AN:

32038

Ashkenazi Jewish (ASJ)

AF:

0.0000519

AC:

AN:

19282

East Asian (EAS)

AF:

0.00

AC:

AN:

21452

South Asian (SAS)

AF:

0.0000389

AC:

AN:

51354

European-Finnish (FIN)

AF:

0.0000232

AC:

AN:

43036

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4340

European-Non Finnish (NFE)

AF:

0.0000660

AC:

AN:

908706

Other (OTH)

AF:

0.0000424

AC:

AN:

47164

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.266

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000156

AC:

AN:

121430

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

AN XY:

58058

show subpopulations

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

African (AFR)

AF:

0.000254

AC:

AN:

39398

American (AMR)

AF:

0.0000901

AC:

AN:

11104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2522

East Asian (EAS)

AF:

0.00

AC:

AN:

2368

South Asian (SAS)

AF:

0.00

AC:

AN:

2286

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

244

European-Non Finnish (NFE)

AF:

0.000150

AC:

AN:

53430

Other (OTH)

AF:

0.00

AC:

AN:

1612

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.357

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000253

Hom.:

ExAC

AF:

0.000126

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.74

(source)

DANN

Benign

0.27

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.61

T;T;T;T;T;T

M_CAP

Benign

0.0026

MetaRNN

Benign

0.033

T;T;T;T;T;T

MetaSVM

Benign

-0.95

PhyloP100

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

0.90

N;N;N;N;N;N

REVEL

Benign

0.043

Sift

Benign

1.0

T;T;T;T;T;T

Sift4G

Benign

0.64

T;T;T;T;T;T

Polyphen

0.025, 0.0090, 0.0

.;B;.;B;B;.

Vest4

0.14

MVP

0.043

MPC

0.24

ClinPred

0.014

GERP RS

1.3

gMVP

0.34

Mutation Taster

=98/2

polymorphism

(source)

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

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rs1053344

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over