6-49606921-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_000324.3(RHAG):c.1139G>A(p.Gly380Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G380V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RHAG
NM_000324.3 missense, splice_region

Scores

Splicing: ADA: 0.9989

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.50

Publications

5 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: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-49606921-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 13066.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHAG	NM_000324.3 link	c.1139G>A	p.Gly380Asp	missense_variant, splice_region_variant	Exon 9 of 10	ENST00000371175.10	NP_000315.2	Q02094-1Q96E98

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RHAG	ENST00000371175.10 link	c.1139G>A	p.Gly380Asp	missense_variant, splice_region_variant	Exon 9 of 10	1	NM_000324.3	ENSP00000360217.4	Q02094-1
RHAG	ENST00000646272.1 link	c.1139G>A	p.Gly380Asp	missense_variant, splice_region_variant	Exon 9 of 10			ENSP00000494337.1	A0A2R8YEH1
RHAG	ENST00000646939.1 link	c.1017G>A	p.Arg339Arg	splice_region_variant, synonymous_variant	Exon 8 of 9			ENSP00000494709.1	Q02094-2
RHAG	ENST00000646963.1 link	c.1138+229G>A		intron_variant	Intron 8 of 8			ENSP00000495337.1	Q9UHG9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250906

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1455690

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724658

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33318

American (AMR)

AF:

0.0000224

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106546

Other (OTH)

AF:

0.0000166

AC:

AN:

60150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.;T

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Benign

-0.46

MutationAssessor

Pathogenic

3.9

H;.;.

PhyloP100

7.5

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-6.5

D;.;.

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0010

D;.;D

Polyphen

1.0

D;.;.

Vest4

0.96

MutPred

0.83

Loss of ubiquitination at K384 (P = 0.063);Loss of ubiquitination at K384 (P = 0.063);Loss of ubiquitination at K384 (P = 0.063);

MVP

0.55

MPC

1.1

ClinPred

1.0

GERP RS

5.9

Varity_R

0.93

gMVP

0.94

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.82

SpliceAI score (max)

0.040

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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6-49606921-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over