6-49611084-A-G

Variant names:

• chr6-49611084-A-G
• rs1554172605
• NM_000324.3:c.1007T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000324.3(RHAG):​c.1007T>C​(p.Leu336Ser) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHAG NM_000324.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 8.86

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: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHAG	NM_000324.3	c.1007T>C	p.Leu336Ser	missense_variant	Exon 7 of 10	ENST00000371175.10	NP_000315.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHAG	ENST00000371175.10	c.1007T>C	p.Leu336Ser	missense_variant	Exon 7 of 10	1	NM_000324.3	ENSP00000360217.4
RHAG	ENST00000646272.1	c.1007T>C	p.Leu336Ser	missense_variant	Exon 7 of 10			ENSP00000494337.1
RHAG	ENST00000646963.1	c.1007T>C	p.Leu336Ser	missense_variant	Exon 7 of 9			ENSP00000495337.1
RHAG	ENST00000646939.1	c.945+1313T>C		intron_variant	Intron 6 of 8			ENSP00000494709.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Overhydrated hereditary stomatocytosis Uncertain:1

Jun 27, 2017

Department of Hematology - Research Laboratory 1, Postgraduate Institute of Medical Education and Research

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

This variant was found in the asymptomatic mother of the index case and is likely to be not pathogenic. NM_000324.2(RHAG):c.1007 T>C was not found in 100 alleles of unrelated hematologically normal individuals. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	T;.;T;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	3.5	M;.;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.9	D;.;.;.;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;D;D;.
Polyphen		0.96	P;.;.;.;D
Vest4		0.79
MutPred		0.75		Gain of disorder (P = 0.0064);Gain of disorder (P = 0.0064);Gain of disorder (P = 0.0064);Gain of disorder (P = 0.0064);Gain of disorder (P = 0.0064);
MVP		0.78
MPC		1.1
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.57
gMVP		0.62

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: rs1554172605; hg19: chr6-49578797;