Genetic Variant RHCE:p.Ile306Val (chr1-25388999-T-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_020485.8(RHCE):c.916A>G(p.Ile306Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,614,034 control chromosomes in the GnomAD database, including 3 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 30)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

RHCE
NM_020485.8 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.292

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005934).

BP6

Variant 1-25388999-T-C is Benign according to our data. Variant chr1-25388999-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 789916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHCE	NM_020485.8 link	c.916A>G	p.Ile306Val	missense_variant	Exon 6 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.916A>G	p.Ile306Val	missense_variant	Exon 6 of 10	1	NM_020485.8	ENSP00000294413.6		P18577

Frequencies

GnomAD3 genomes

AF:

0.00173

AC:

263

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00529

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

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:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000466

AC:

117

AN:

251280

Hom.:

AF XY:

0.000420

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.00419

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000293

AC:

429

AN:

1461800

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

172

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00666

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000881

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.00182

AC:

277

AN:

152234

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00558

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000413

Hom.:

Bravo

AF:

0.00194

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000511

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 24, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

5.5

DANN

Benign

0.65

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.57

T;T;T;T;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.0059

T;T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.21

N;N;N;N;N

REVEL

Benign

0.046

Sift

Benign

0.72

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.074, 0.0010

.;B;.;B;.

Vest4

0.14

MVP

0.11

MPC

0.25

ClinPred

0.0054

GERP RS

2.5

gMVP

0.068

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over