1-25284746-A-G

Variant names:

• chr1-25284746-A-G
• rs1307899222
• NM_016124.6:c.322A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016124.6(RHD):​c.322A>G​(p.Ile108Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,254,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: RHD NM_016124.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.668

Genes affected

RHD (HGNC:10009): (Rh blood group D antigen) The Rh blood group system is the second most clinically significant of the blood groups, second only to ABO. It is also the most polymorphic of the blood groups, with variations due to deletions, gene conversions, and missense mutations. The Rh blood group includes this gene, which encodes the RhD protein, and a second gene that encodes both the RhC and RhE antigens on a single polypeptide. The two genes, and a third unrelated gene, are found in a cluster on chromosome 1. The classification of Rh-positive and Rh-negative individuals is determined by the presence or absence of the highly immunogenic RhD protein on the surface of erythrocytes. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RSRP1 (HGNC:25234): (arginine and serine rich protein 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20799512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHD	NM_016124.6	c.322A>G	p.Ile108Val	missense_variant	Exon 2 of 10	ENST00000328664.9	NP_057208.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHD	ENST00000328664.9	c.322A>G	p.Ile108Val	missense_variant	Exon 2 of 10	1	NM_016124.6	ENSP00000331871.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000443 AC: 1 AN: 225512 Hom.: 0 AF XY: 0.00000823 AC XY: 1 AN XY: 121520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000302

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000558 AC: 7 AN: 1254174 Hom.: 0 Cov.: 34 AF XY: 0.00000959 AC XY: 6 AN XY: 625580

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000703

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: 0.00000323

Gnomad4 OTH exome AF: 0.0000187

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.322A>G (p.I108V) alteration is located in exon 2 (coding exon 2) of the RHD gene. This alteration results from a A to G substitution at nucleotide position 322, causing the isoleucine (I) at amino acid position 108 to be replaced by a valine (V). 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	0.15
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.5
DANN	Benign	0.65
DEOGEN2	Benign	0.0030	T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;.
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.;.;L;L;L;.;L;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.65	N;.;.;N;N;N;N;N;N
REVEL	Benign	0.038
Sift	Benign	0.12	T;.;.;T;T;T;T;T;T
Sift4G	Benign	0.47	T;.;T;T;T;T;T;T;T
Polyphen		0.16	B;.;P;.;.;.;.;.;P
Vest4		0.40
MutPred		0.52		Loss of methylation at K105 (P = 0.1188);Loss of methylation at K105 (P = 0.1188);Loss of methylation at K105 (P = 0.1188);Loss of methylation at K105 (P = 0.1188);Loss of methylation at K105 (P = 0.1188);Loss of methylation at K105 (P = 0.1188);Loss of methylation at K105 (P = 0.1188);Loss of methylation at K105 (P = 0.1188);Loss of methylation at K105 (P = 0.1188);
MVP		0.16
MPC		0.27
ClinPred		0.097	T
GERP RS		1.8
Varity_R		0.038
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs1307899222; hg19: chr1-25611237;