rs16879498

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBA1

The NM_000324.3(RHAG):c.808G>A(p.Val270Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0332 in 1,613,752 control chromosomes in the GnomAD database, including 1,346 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 176 hom., cov: 32)

Exomes 𝑓: 0.032 ( 1170 hom. )

Consequence

RHAG
NM_000324.3 missense, splice_region

Scores

Splicing: ADA: 0.9998

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 5.06

Variant links:

Genes affected

RHAG (HGNC:10006): (Rh associated glycoprotein) The protein encoded by this gene is erythrocyte-specific and is thought to be part of a membrane channel that transports ammonium and carbon dioxide across the blood cell membrane. The encoded protein appears to interact with Rh blood group antigens and Rh30 polypeptides. Defects in this gene are a cause of regulator type Rh-null hemolytic anemia (RHN), or Rh-deficiency syndrome.[provided by RefSeq, Mar 2009]

RHAG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 6-49612534-C-T is Benign according to our data. Variant chr6-49612534-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 225454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49612534-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0983 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHAG	NM_000324.3 link	c.808G>A	p.Val270Ile	missense_variant, splice_region_variant	Exon 6 of 10	ENST00000371175.10	NP_000315.2	Q02094-1Q96E98

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHAG	ENST00000371175.10 link	c.808G>A	p.Val270Ile	missense_variant, splice_region_variant	Exon 6 of 10	1	NM_000324.3	ENSP00000360217.4		Q02094-1

Frequencies

GnomAD3 genomes

AF:

0.0419

AC:

6368

AN:

152130

Hom.:

173

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0731

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0328

Gnomad ASJ

AF:

0.0502

Gnomad EAS

AF:

0.0580

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.0127

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0238

Gnomad OTH

AF:

0.0416

GnomAD3 exomes

AF:

0.0421

AC:

10569

AN:

251276

Hom.:

346

AF XY:

0.0427

AC XY:

5799

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.0727

Gnomad AMR exome

AF:

0.0471

Gnomad ASJ exome

AF:

0.0462

Gnomad EAS exome

AF:

0.0623

Gnomad SAS exome

AF:

0.0988

Gnomad FIN exome

AF:

0.0121

Gnomad NFE exome

AF:

0.0236

Gnomad OTH exome

AF:

0.0303

GnomAD4 exome

AF:

0.0323

AC:

47200

AN:

1461506

Hom.:

1170

Cov.:

AF XY:

0.0339

AC XY:

24632

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.0761

Gnomad4 AMR exome

AF:

0.0445

Gnomad4 ASJ exome

AF:

0.0460

Gnomad4 EAS exome

AF:

0.0505

Gnomad4 SAS exome

AF:

0.0969

Gnomad4 FIN exome

AF:

0.0127

Gnomad4 NFE exome

AF:

0.0252

Gnomad4 OTH exome

AF:

0.0362

GnomAD4 genome

AF:

0.0419

AC:

6382

AN:

152246

Hom.:

176

Cov.:

AF XY:

0.0423

AC XY:

3148

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0731

Gnomad4 AMR

AF:

0.0328

Gnomad4 ASJ

AF:

0.0502

Gnomad4 EAS

AF:

0.0584

Gnomad4 SAS

AF:

0.106

Gnomad4 FIN

AF:

0.0127

Gnomad4 NFE

AF:

0.0238

Gnomad4 OTH

AF:

0.0445

Alfa

AF:

0.0303

Hom.:

184

Bravo

AF:

0.0437

TwinsUK

AF:

0.0248

AC:

ALSPAC

AF:

0.0265

AC:

102

ESP6500AA

AF:

0.0670

AC:

295

ESP6500EA

AF:

0.0271

AC:

233

ExAC

AF:

0.0434

AC:

5269

Asia WGS

AF:

0.0770

AC:

265

AN:

3478

EpiCase

AF:

0.0250

EpiControl

AF:

0.0242

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Rh-null, regulator type

Benign:2Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Pathogenic and reported on 05-03-2012 by Lab or GTR ID 504843. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

The homozygous p.Val270Ile variant in RHAG has been reported in an individual with cosanguineous parents and Rh-null syndrome (PMID: 10467273). Of note, this variant was found in cis with p.Gly280Arg in RHAG in this individual (PMID: 10467273). This variant has also been identified in >10% of South Asian chromosomes and 176 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for Rh-null syndrome. -

Rh-null, regulator type;C1861455:Overhydrated hereditary stomatocytosis

Benign:1

Jul 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

T;.;.;T;T;.

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.82

T;T;T;T;T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.0038

T;T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.8

M;.;M;.;.;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.99

N;.;.;.;N;.

REVEL

Uncertain

0.30

Sift

Uncertain

0.0020

D;.;.;.;T;.

Sift4G

Uncertain

0.030

D;.;.;D;D;.

Polyphen

0.91

P;.;.;.;.;P

Vest4

0.20

MPC

0.48

ClinPred

0.025

GERP RS

5.5

Varity_R

0.25

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.030

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