6-49607181-G-C

Variant names:

• chr6-49607181-G-C
• rs141568382
• NM_000324.3:c.1107C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000324.3(RHAG):​c.1107C>G​(p.Ile369Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I369I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RHAG NM_000324.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• Publications: 0 publications found

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]

RHAG Gene-Disease associations (from GenCC):

• Rh deficiency syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• overhydrated hereditary stomatocytosis

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20606297).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000324.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHAG	NM_000324.3	MANE Select	c.1107C>G	p.Ile369Met	missense	Exon 8 of 10	NP_000315.2	Q02094-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHAG	ENST00000371175.10	TSL:1 MANE Select	c.1107C>G	p.Ile369Met	missense	Exon 8 of 10	ENSP00000360217.4	Q02094-1
	RHAG	ENST00000646272.1		c.1107C>G	p.Ile369Met	missense	Exon 8 of 10	ENSP00000494337.1	A0A2R8YEH1
	RHAG	ENST00000646963.1		c.1107C>G	p.Ile369Met	missense	Exon 8 of 9	ENSP00000495337.1	Q9UHG9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461392 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726978

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111724

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.072	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-1.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.14
Sift	Benign	0.044	D
Sift4G	Uncertain	0.049	D
Polyphen		0.24	B
Vest4		0.40
MutPred		0.59		Gain of disorder (P = 0.0289)
MVP		0.14
MPC		0.90
ClinPred		0.93	D
GERP RS		-5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.35
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141568382; hg19: chr6-49574894;