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GeneBe

6-49606921-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_000324.3(RHAG):c.1139G>T(p.Gly380Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

RHAG
NM_000324.3 missense, splice_region

Scores

9
5
5
Splicing: ADA: 0.9996
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.50
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 6-49606921-C-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RHAGNM_000324.3 linkuse as main transcriptc.1139G>T p.Gly380Val missense_variant, splice_region_variant 9/10 ENST00000371175.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RHAGENST00000371175.10 linkuse as main transcriptc.1139G>T p.Gly380Val missense_variant, splice_region_variant 9/101 NM_000324.3 P2Q02094-1
RHAGENST00000646272.1 linkuse as main transcriptc.1139G>T p.Gly380Val missense_variant, splice_region_variant 9/10 A2
RHAGENST00000646939.1 linkuse as main transcriptc.1017G>T p.Arg339Ser missense_variant, splice_region_variant 8/9 Q02094-2
RHAGENST00000646963.1 linkuse as main transcriptc.1138+229G>T intron_variant

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Rh-null, regulator type Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 1999- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
Cadd
Pathogenic
29
Dann
Uncertain
0.99
DEOGEN2
Benign
0.12
T;.;T
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.79
T;T;T
M_CAP
Benign
0.071
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Benign
-0.38
T
MutationAssessor
Pathogenic
3.9
H;.;.
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.53
T
PROVEAN
Pathogenic
-8.2
D;.;.
REVEL
Uncertain
0.60
Sift
Uncertain
0.0010
D;.;.
Sift4G
Pathogenic
0.0010
D;.;D
Polyphen
1.0
D;.;.
Vest4
0.89
MutPred
0.88
Gain of methylation at K384 (P = 0.0989);Gain of methylation at K384 (P = 0.0989);Gain of methylation at K384 (P = 0.0989);
MVP
0.60
MPC
1.0
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.94
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.98
SpliceAI score (max)
0.58
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.58
Position offset: 0

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.

Other links and lift over

dbSNP: rs121918589; hg19: chr6-49574634; API