6-49607194-A-C

Variant names:

• chr6-49607194-A-C
• NM_000324.3:c.1094T>G

Variant summary

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

The NM_000324.3(RHAG):​c.1094T>G​(p.Leu365Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RHAG NM_000324.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.42

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, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHAG	NM_000324.3	c.1094T>G	p.Leu365Arg	missense_variant	Exon 8 of 10	ENST00000371175.10	NP_000315.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHAG	ENST00000371175.10	c.1094T>G	p.Leu365Arg	missense_variant	Exon 8 of 10	1	NM_000324.3	ENSP00000360217.4
RHAG	ENST00000646272.1	c.1094T>G	p.Leu365Arg	missense_variant	Exon 8 of 10			ENSP00000494337.1
RHAG	ENST00000646963.1	c.1094T>G	p.Leu365Arg	missense_variant	Exon 8 of 9			ENSP00000495337.1
RHAG	ENST00000646939.1	c.972T>G	p.Thr324Thr	synonymous_variant	Exon 7 of 9			ENSP00000494709.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461450 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727010

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 02, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;T;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.7	H;.;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.4	D;.;.;.;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;.;D;D;.
Polyphen		1.0	D;.;.;.;D
Vest4		0.92
MutPred		0.88		Gain of methylation at L365 (P = 0.0059);Gain of methylation at L365 (P = 0.0059);Gain of methylation at L365 (P = 0.0059);Gain of methylation at L365 (P = 0.0059);Gain of methylation at L365 (P = 0.0059);
MVP		0.46
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-49574907;