Genetic Variant RHCE:p.Thr342Ile (chr1-25385759-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020485.8(RHCE):c.1025C>T(p.Thr342Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,613,736 control chromosomes in the GnomAD database, including 10 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 4 hom., cov: 31)

Exomes 𝑓: 0.00074 ( 6 hom. )

Consequence

RHCE
NM_020485.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.417

Publications

0 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00818634).

BP6

Variant 1-25385759-G-A is Benign according to our data. Variant chr1-25385759-G-A is described in ClinVar as Benign. ClinVar VariationId is 791109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0063 (958/151988) while in subpopulation AFR AF = 0.0196 (814/41446). AF 95% confidence interval is 0.0185. There are 4 homozygotes in GnomAd4. There are 484 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RHCE	NM_020485.8	MANE Select	c.1025C>T	p.Thr342Ile	missense	Exon 7 of 10	NP_065231.4	P18577-1
RHCE	NM_001330430.4		c.1025C>T	p.Thr342Ile	missense	Exon 7 of 9	NP_001317359.1
RHCE	NM_138617.5		c.710C>T	p.Thr237Ile	missense	Exon 5 of 7	NP_619523.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RHCE	ENST00000294413.13	TSL:1 MANE Select	c.1025C>T	p.Thr342Ile	missense	Exon 7 of 10	ENSP00000294413.6	P18577-1
RHCE	ENST00000413854.5	TSL:1	c.1025C>T	p.Thr342Ile	missense	Exon 7 of 9	ENSP00000415417.2	E7EU00
RHCE	ENST00000340849.8	TSL:1	c.710C>T	p.Thr237Ile	missense	Exon 5 of 7	ENSP00000345084.4	P18577-3

Frequencies

GnomAD3 genomes

AF:

0.00631

AC:

958

AN:

151870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0197

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00623

Gnomad ASJ

AF:

0.00377

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00480

GnomAD2 exomes

AF:

0.00181

AC:

455

AN:

251450

AF XY:

0.00137

show subpopulations

Gnomad AFR exome

AF:

0.0198

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.00328

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000744

AC:

1088

AN:

1461748

Hom.:

Cov.:

AF XY:

0.000666

AC XY:

484

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.0174

AC:

584

AN:

33472

American (AMR)

AF:

0.00186

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00338

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000185

AC:

206

AN:

1111966

Other (OTH)

AF:

0.00186

AC:

112

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

166

249

332

415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00630

AC:

958

AN:

151988

Hom.:

Cov.:

AF XY:

0.00652

AC XY:

484

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.0196

AC:

814

AN:

41446

American (AMR)

AF:

0.00622

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00377

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68012

Other (OTH)

AF:

0.00475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00284

Hom.:

Bravo

AF:

0.00690

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0172

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00212

AC:

257

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.16

(source)

DANN

Benign

0.84

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0082

MetaSVM

Benign

-0.99

PhyloP100

-0.42

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.5

REVEL

Benign

0.0080

Sift

Benign

0.63

Sift4G

Benign

0.15

Polyphen

0.0050

Vest4

0.11

MVP

0.14

MPC

0.32

ClinPred

0.0028

GERP RS

-3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.27

Mutation Taster

=91/9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over