chr6-49612534-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

Rh deficiency syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
overhydrated hereditary stomatocytosis
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

RHAG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PP3

Splicing predictors support a deleterious 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 Benign/Likely_benign. ClinVar VariationId is 225454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000324.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHAG	NM_000324.3	MANE Select	c.808G>A	p.Val270Ile	missense splice_region	Exon 6 of 10	NP_000315.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RHAG	ENST00000371175.10	TSL:1 MANE Select	c.808G>A	p.Val270Ile	missense splice_region	Exon 6 of 10	ENSP00000360217.4
RHAG	ENST00000646272.1		c.808G>A	p.Val270Ile	missense splice_region	Exon 6 of 10	ENSP00000494337.1
RHAG	ENST00000646963.1		c.808G>A	p.Val270Ile	missense splice_region	Exon 6 of 9	ENSP00000495337.1

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

GnomAD2 exomes

AF:

0.0421

AC:

10569

AN:

251276

AF XY:

0.0427

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 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

African (AFR)

AF:

0.0761

AC:

2545

AN:

33452

American (AMR)

AF:

0.0445

AC:

1988

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0460

AC:

1203

AN:

26128

East Asian (EAS)

AF:

0.0505

AC:

2006

AN:

39698

South Asian (SAS)

AF:

0.0969

AC:

8355

AN:

86238

European-Finnish (FIN)

AF:

0.0127

AC:

680

AN:

53412

Middle Eastern (MID)

AF:

0.0403

AC:

232

AN:

5762

European-Non Finnish (NFE)

AF:

0.0252

AC:

28005

AN:

1111726

Other (OTH)

AF:

0.0362

AC:

2186

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

2586

5172

7759

10345

12931

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1242

2484

3726

4968

6210

<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:

0.0419

AC:

6382

AN:

152246

Hom.:

176

Cov.:

AF XY:

0.0423

AC XY:

3148

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0731

AC:

3035

AN:

41538

American (AMR)

AF:

0.0328

AC:

502

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0502

AC:

174

AN:

3468

East Asian (EAS)

AF:

0.0584

AC:

302

AN:

5174

South Asian (SAS)

AF:

0.106

AC:

511

AN:

4824

European-Finnish (FIN)

AF:

0.0127

AC:

135

AN:

10610

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0238

AC:

1617

AN:

68020

Other (OTH)

AF:

0.0445

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

313

627

940

1254

1567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0336

Hom.:

316

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.82

M_CAP

Benign

0.033

MetaRNN

Benign

0.0038

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.8

PhyloP100

5.1

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.99

REVEL

Uncertain

0.30

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.030

Polyphen

0.91

Vest4

0.20

MPC

0.48

ClinPred

0.025

GERP RS

5.5

Varity_R

0.25

gMVP

0.38

Mutation Taster

=17/83

polymorphism (auto)

(source)

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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over