chr6-49607180-C-T

Variant names:

• chr6-49607180-C-T
• rs751577470
• NM_000324.3:c.1108G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000324.3(RHAG):​c.1108G>A​(p.Gly370Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RHAG NM_000324.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.33
• Publications: 3 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• overhydrated hereditary stomatocytosis

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-49607180-C-T is Pathogenic according to our data. Variant chr6-49607180-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2244914.

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.1108G>A	p.Gly370Arg	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.1108G>A	p.Gly370Arg	missense	Exon 8 of 10	ENSP00000360217.4	Q02094-1
	RHAG	ENST00000646272.1		c.1108G>A	p.Gly370Arg	missense	Exon 8 of 10	ENSP00000494337.1	A0A2R8YEH1
	RHAG	ENST00000646963.1		c.1108G>A	p.Gly370Arg	missense	Exon 8 of 9	ENSP00000495337.1	Q9UHG9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250452 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461496 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727042

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111824

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000612 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
1	-	-	Rh-null, regulator type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.056
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		4.3
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.28
Sift	Benign	0.038	D
Sift4G	Benign	0.063	T
Polyphen		1.0	D
Vest4		0.72
MutPred		0.82		Gain of methylation at G370 (P = 0.0092)
MVP		0.30
MPC		1.0
ClinPred		0.98	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.86
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs751577470; hg19: chr6-49574893;