6-49612504-C-T

Position:

• chr6-49612504-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000324.3(RHAG):​c.838G>A​(p.Gly280Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RHAG NM_000324.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHAG	NM_000324.3	c.838G>A	p.Gly280Arg	missense_variant	6/10	ENST00000371175.10	NP_000315.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHAG	ENST00000371175.10	c.838G>A	p.Gly280Arg	missense_variant	6/10	1	NM_000324.3	ENSP00000360217	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727210

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T;.;.;T;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.9	H;.;H;.;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.6	D;.;.;.;D;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0050	D;.;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;D;.
Polyphen		1.0	D;.;.;.;.;D
Vest4		0.99
MutPred		0.93		Gain of methylation at G280 (P = 0.0056);Gain of methylation at G280 (P = 0.0056);Gain of methylation at G280 (P = 0.0056);Gain of methylation at G280 (P = 0.0056);Gain of methylation at G280 (P = 0.0056);Gain of methylation at G280 (P = 0.0056);
MVP		0.70
MPC		1.0
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.82
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs104893987; hg19: chr6-49580217;