NM_000324.3:c.1163G>A

Variant names:

• chr6-49606897-C-T
• NM_000324.3:c.1163G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000324.3(RHAG):​c.1163G>A​(p.Trp388*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RHAG NM_000324.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.84

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0545 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-49606897-C-T is Pathogenic according to our data. Variant chr6-49606897-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3725598.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHAG	NM_000324.3	c.1163G>A	p.Trp388*	stop_gained	Exon 9 of 10	ENST00000371175.10	NP_000315.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHAG	ENST00000371175.10	c.1163G>A	p.Trp388*	stop_gained	Exon 9 of 10	1	NM_000324.3	ENSP00000360217.4
RHAG	ENST00000646272.1	c.1163G>A	p.Trp388*	stop_gained	Exon 9 of 10			ENSP00000494337.1
RHAG	ENST00000646939.1	c.1041G>A	p.Leu347Leu	synonymous_variant	Exon 8 of 9			ENSP00000494709.1
RHAG	ENST00000646963.1	c.1138+253G>A		intron_variant	Intron 8 of 8			ENSP00000495337.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp388*) in the RHAG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RHAG are known to be pathogenic (PMID: 9759472, 28470789). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RHAG-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	36
DANN	Benign	0.93
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.81	D
Vest4		0.81
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: chr6-49574610;