6-49606921-C-A

Position:

• chr6-49606921-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

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. 3/3 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: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.50

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 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, max_spliceai. 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
RHAG	NM_000324.3	c.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
RHAG	ENST00000371175.10	c.1139G>T	p.Gly380Val	missense_variant, splice_region_variant	9/10	1	NM_000324.3	P2
RHAG	ENST00000646272.1	c.1139G>T	p.Gly380Val	missense_variant, splice_region_variant	9/10			A2
RHAG	ENST00000646939.1	c.1017G>T	p.Arg339Ser	missense_variant, splice_region_variant	8/9
RHAG	ENST00000646963.1	c.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

Submissions by phenotype

Rh-null, regulator type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 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

Other links and lift over

dbSNP: rs121918589; hg19: chr6-49574634;