6-49607180-C-T

Position:

chr6-49607180-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_000324.3(RHAG):c.1108G>A(p.Gly370Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RHAG
NM_000324.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 4.33

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-49607180-C-T is Pathogenic according to our data. Variant chr6-49607180-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2244914.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHAG	NM_000324.3 linkuse as main transcript	c.1108G>A	p.Gly370Arg	missense_variant	8/10	ENST00000371175.10	NP_000315.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHAG	ENST00000371175.10 linkuse as main transcript	c.1108G>A	p.Gly370Arg	missense_variant	8/10	1	NM_000324.3	ENSP00000360217	P2	Q02094-1
RHAG	ENST00000646272.1 linkuse as main transcript	c.1108G>A	p.Gly370Arg	missense_variant	8/10			ENSP00000494337	A2
RHAG	ENST00000646963.1 linkuse as main transcript	c.1108G>A	p.Gly370Arg	missense_variant	8/9			ENSP00000495337
RHAG	ENST00000646939.1 linkuse as main transcript	c.986G>A	p.Arg329Gln	missense_variant	7/9			ENSP00000494709		Q02094-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250452

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135324

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461496

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000612

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Rh-null, regulator type

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 09, 2024

Variant summary: RHAG c.1108G>A (p.Gly370Arg) results in a non-conservative amino acid change located in the Ammonium transporter AmtB-like domain (IPR024041) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250452 control chromosomes. c.1108G>A has been reported in the literature in homozygous individuals affected with Rh-Null, Regulator Type (e.g. dePaulaVendrame_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36093570). ClinVar contains an entry for this variant (Variation ID: 2244914). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.1108G>A (p.G370R) alteration is located in exon 8 (coding exon 8) of the RHAG gene. This alteration results from a G to A substitution at nucleotide position 1108, causing the glycine (G) at amino acid position 370 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.;T;T;.

Eigen

Benign

0.056

Eigen_PC

Benign

0.079

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.89

D;D;D;D;D

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.56

D;D;D;D;D

MetaSVM

Benign

-0.99

MutationAssessor

Pathogenic

3.5

M;.;.;.;.

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.6

D;.;.;.;.

REVEL

Benign

0.28

Sift

Benign

0.038

D;.;.;.;.

Sift4G

Benign

0.063

T;.;D;T;.

Polyphen

1.0

D;.;.;.;D

Vest4

0.72

MutPred

0.82

Gain of methylation at G370 (P = 0.0092);Gain of methylation at G370 (P = 0.0092);Gain of methylation at G370 (P = 0.0092);Gain of methylation at G370 (P = 0.0092);Gain of methylation at G370 (P = 0.0092);

MVP

0.30

MPC

1.0

ClinPred

0.98

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.34

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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