rs121918588

chr6-49636810-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_000324.3(RHAG):c.3G>T(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000093 in 1,613,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: RHAG NM_000324.3 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.34

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 9 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PP5: Variant 6-49636810-C-A is Pathogenic according to our data. Variant chr6-49636810-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 13063.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.3G>T	p.Met1?	start_lost	1/10	ENST00000371175.10
RHAG	XM_011514788.2	c.3G>T	p.Met1?	start_lost	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHAG	ENST00000371175.10	c.3G>T	p.Met1?	start_lost	1/10	1	NM_000324.3	P2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250814 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135560

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461480 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000421

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 AF: 0.00000658 AC: 1 AN: 152050 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74268

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000160 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Rh mod blood group phenotype Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.027	T;.;.;T;T;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.94	A;A
PROVEAN	Benign	-2.1	N;.;.;.;N;.
REVEL	Uncertain	0.29
Sift	Benign	0.20	T;.;.;.;T;.
Sift4G	Benign	0.17	T;.;.;T;T;.
Polyphen		0.10	B;.;.;.;.;B
Vest4		0.95
MutPred		0.96		Gain of catalytic residue at M1 (P = 0.0247);Gain of catalytic residue at M1 (P = 0.0247);Gain of catalytic residue at M1 (P = 0.0247);Gain of catalytic residue at M1 (P = 0.0247);Gain of catalytic residue at M1 (P = 0.0247);Gain of catalytic residue at M1 (P = 0.0247);
MVP		0.31
ClinPred		0.74	D
GERP RS		5.5
Varity_R		0.42
gMVP		0.25

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: rs121918588; hg19: chr6-49604523;