1-25301552-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016124.6(RHD):c.667T>G(p.Phe223Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00734 in 1,378,402 control chromosomes in the GnomAD database, including 2,067 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency:
  • Genomes: 𝑓 0.034 (801 hom., cov: 21)
  • Exomes 𝑓: 0.0045 (1266 hom.)
• Consequence: RHD NM_016124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.41

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007235974).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHD	NM_016124.6	c.667T>G	p.Phe223Val	missense_variant	5/10	ENST00000328664.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHD	ENST00000328664.9	c.667T>G	p.Phe223Val	missense_variant	5/10	1	NM_016124.6	P1

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 4427 AN: 131638 Hom.: 796 Cov.: 21

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00446

Gnomad EAS AF: 0.00195

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000226

Gnomad MID AF: 0.0111

Gnomad NFE AF: 0.000986

Gnomad OTH AF: 0.0296

GnomAD3 exomes AF: 0.0103 AC: 2328 AN: 225016 Hom.: 506 AF XY: 0.00847 AC XY: 1027 AN XY: 121250

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00784

Gnomad ASJ exome AF: 0.00370

Gnomad EAS exome AF: 0.00245

Gnomad SAS exome AF: 0.00335

Gnomad FIN exome AF: 0.000105

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00622

GnomAD4 exome AF: 0.00454 AC: 5663 AN: 1246646 Hom.: 1266 Cov.: 31 AF XY: 0.00418 AC XY: 2601 AN XY: 621870

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.00960

Gnomad4 ASJ exome AF: 0.00391

Gnomad4 EAS exome AF: 0.00106

Gnomad4 SAS exome AF: 0.00344

Gnomad4 FIN exome AF: 0.0000850

Gnomad4 NFE exome AF: 0.000698

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.0338 AC: 4454 AN: 131756 Hom.: 801 Cov.: 21 AF XY: 0.0315 AC XY: 2030 AN XY: 64500

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.00446

Gnomad4 EAS AF: 0.00195

Gnomad4 SAS AF: 0.00183

Gnomad4 FIN AF: 0.000226

Gnomad4 NFE AF: 0.000986

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0291 Hom.: 75

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.0905 AC: 384

ESP6500EA AF: 0.00213 AC: 16

ExAC AF: 0.0118 AC: 1331

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Benign	0.13	T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.62	T;T;T;T;T;T;T;T;.
MetaRNN	Benign	0.0072	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.8	M;.;.;M;M;M;.;M;.
MutationTaster	Benign	0.000029	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.1	D;.;.;D;D;D;D;D;D
REVEL	Benign	0.28
Sift	Benign	0.22	T;.;.;T;T;T;T;T;T
Sift4G	Uncertain	0.059	T;.;D;T;T;T;D;D;D
Polyphen		0.025	B;.;D;.;.;.;.;.;D
Vest4		0.58
MPC		0.16
ClinPred		0.076	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.81

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: rs1053356; hg19: chr1-25628043;