NM_000324.3:c.1194T>A

Variant names:

• chr6-49606866-A-T
• NM_000324.3:c.1194T>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000324.3(RHAG):​c.1194T>A​(p.Asp398Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RHAG NM_000324.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28993452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHAG	NM_000324.3	c.1194T>A	p.Asp398Glu	missense_variant	Exon 9 of 10	ENST00000371175.10	NP_000315.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHAG	ENST00000371175.10	c.1194T>A	p.Asp398Glu	missense_variant	Exon 9 of 10	1	NM_000324.3	ENSP00000360217.4
RHAG	ENST00000646272.1	c.1194T>A	p.Asp398Glu	missense_variant	Exon 9 of 10			ENSP00000494337.1
RHAG	ENST00000646939	c.*16T>A		3_prime_UTR_variant	Exon 8 of 9			ENSP00000494709.1
RHAG	ENST00000646963.1	c.1138+284T>A		intron_variant	Intron 8 of 8			ENSP00000495337.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456392 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724882

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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 specified Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1194T>A (p.D398E) alteration is located in exon 9 (coding exon 9) of the RHAG gene. This alteration results from a T to A substitution at nucleotide position 1194, causing the aspartic acid (D) at amino acid position 398 to be replaced by a glutamic acid (E). 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	Benign	0.17
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.015	T;.;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.63	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.2	N;.;.
REVEL	Benign	0.17
Sift	Benign	0.79	T;.;.
Sift4G	Benign	0.61	T;.;T
Polyphen		0.0040	B;.;.
Vest4		0.20
MutPred		0.75		Gain of catalytic residue at D398 (P = 0.0519);Gain of catalytic residue at D398 (P = 0.0519);Gain of catalytic residue at D398 (P = 0.0519);
MVP		0.41
MPC		0.62
ClinPred		0.82	D
GERP RS		4.7
Varity_R		0.10
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-49574579;