chr6-49607180-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 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 id is 2244914.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHAG	NM_000324.3	c.1108G>A	p.Gly370Arg	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.1108G>A	p.Gly370Arg	missense_variant	Exon 8 of 10	1	NM_000324.3	ENSP00000360217.4
RHAG	ENST00000646272.1	c.1108G>A	p.Gly370Arg	missense_variant	Exon 8 of 10			ENSP00000494337.1
RHAG	ENST00000646963.1	c.1108G>A	p.Gly370Arg	missense_variant	Exon 8 of 9			ENSP00000495337.1
RHAG	ENST00000646939.1	c.986G>A	p.Arg329Gln	missense_variant	Exon 7 of 9			ENSP00000494709.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250452 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135324

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000612 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rh-null, regulator type Pathogenic:1

Jul 09, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RHAG c.1108G>A (p.Gly370Arg) results in a non-conservative amino acid change located in the Ammonium transporter AmtB-like domain (IPR024041) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250452 control chromosomes. c.1108G>A has been reported in the literature in homozygous individuals affected with Rh-Null, Regulator Type (e.g. dePaulaVendrame_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36093570). ClinVar contains an entry for this variant (Variation ID: 2244914). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not specified Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1108G>A (p.G370R) alteration is located in exon 8 (coding exon 8) of the RHAG gene. This alteration results from a G to A substitution at nucleotide position 1108, causing the glycine (G) at amino acid position 370 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;.;T;T;.
Eigen	Benign	0.056
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.56	D;D;D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Pathogenic	3.5	M;.;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.6	D;.;.;.;.
REVEL	Benign	0.28
Sift	Benign	0.038	D;.;.;.;.
Sift4G	Benign	0.063	T;.;D;T;.
Polyphen		1.0	D;.;.;.;D
Vest4		0.72
MutPred		0.82		Gain of methylation at G370 (P = 0.0092);Gain of methylation at G370 (P = 0.0092);Gain of methylation at G370 (P = 0.0092);Gain of methylation at G370 (P = 0.0092);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs751577470; hg19: chr6-49574893;