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GeneBe

6-49607194-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000324.3(RHAG):c.1094T>G(p.Leu365Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RHAG
NM_000324.3 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.42
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RHAGNM_000324.3 linkuse as main transcriptc.1094T>G p.Leu365Arg missense_variant 8/10 ENST00000371175.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RHAGENST00000371175.10 linkuse as main transcriptc.1094T>G p.Leu365Arg missense_variant 8/101 NM_000324.3 P2Q02094-1
RHAGENST00000646272.1 linkuse as main transcriptc.1094T>G p.Leu365Arg missense_variant 8/10 A2
RHAGENST00000646963.1 linkuse as main transcriptc.1094T>G p.Leu365Arg missense_variant 8/9
RHAGENST00000646939.1 linkuse as main transcriptc.972T>G p.Thr324= synonymous_variant 7/9 Q02094-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461450
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727010
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 02, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.17
Cadd
Pathogenic
26
Dann
Uncertain
1.0
DEOGEN2
Benign
0.23
T;.;T;T;.
Eigen
Pathogenic
0.72
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.87
D;D;D;D;D
M_CAP
Benign
0.065
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Benign
-0.36
T
MutationAssessor
Pathogenic
3.7
H;.;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-4.4
D;.;.;.;.
REVEL
Uncertain
0.64
Sift
Uncertain
0.0010
D;.;.;.;.
Sift4G
Pathogenic
0.0010
D;.;D;D;.
Polyphen
1.0
D;.;.;.;D
Vest4
0.92
MutPred
0.88
Gain of methylation at L365 (P = 0.0059);Gain of methylation at L365 (P = 0.0059);Gain of methylation at L365 (P = 0.0059);Gain of methylation at L365 (P = 0.0059);Gain of methylation at L365 (P = 0.0059);
MVP
0.46
MPC
1.1
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.83
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-49574907; API