rs1053362

chr1-25301629-C-Achr1-25301629-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016124.6(RHD):c.744C>A(p.Ser248Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S248S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 21)
• Consequence: RHD NM_016124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.234

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHD	NM_016124.6	c.744C>A	p.Ser248Arg	missense_variant	5/10	ENST00000328664.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHD	ENST00000328664.9	c.744C>A	p.Ser248Arg	missense_variant	5/10	1	NM_016124.6	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.046	N
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;.
M_CAP	Benign	0.0070	T
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Pathogenic	3.2	M;.;.;M;M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.2	D;.;.;D;D;D;D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D;.;.;D;D;D;D;D;D
Sift4G	Benign	0.063	T;.;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.;.;.;D
Vest4		0.87
MutPred		0.80		Loss of catalytic residue at S248 (P = 0.0269);Loss of catalytic residue at S248 (P = 0.0269);Loss of catalytic residue at S248 (P = 0.0269);Loss of catalytic residue at S248 (P = 0.0269);Loss of catalytic residue at S248 (P = 0.0269);Loss of catalytic residue at S248 (P = 0.0269);Loss of catalytic residue at S248 (P = 0.0269);Loss of catalytic residue at S248 (P = 0.0269);Loss of catalytic residue at S248 (P = 0.0269);
MVP		0.28
MPC		0.50
ClinPred		0.99	D
GERP RS		0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.65
gMVP		0.96

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: rs1053362; hg19: chr1-25628120;