rs146093871

Positions:

• chr1-25306719-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_016124.6(RHD):​c.1063G>A​(p.Gly355Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000705 in 1,377,480 control chromosomes in the GnomAD database, including 285 homozygotes. 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 risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.00055 (24 hom., cov: 21)
  • Exomes 𝑓: 0.00072 (261 hom.)
• Consequence: RHD NM_016124.6 missense
• Clinical Significance: risk factor no assertion criteria provided O:2
• Conservation: PhyloP100: -0.998

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011280596).
• BS2: High Homozygotes in GnomAd4 at 24 BG geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHD	NM_016124.6	c.1063G>A	p.Gly355Ser	missense_variant	7/10	ENST00000328664.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHD	ENST00000328664.9	c.1063G>A	p.Gly355Ser	missense_variant	7/10	1	NM_016124.6	P1

Frequencies

GnomAD3 genomes AF: 0.000550 AC: 72 AN: 130878 Hom.: 24 Cov.: 21

Gnomad AFR AF: 0.0000528

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000665

Gnomad ASJ AF: 0.00256

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000935

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000636 AC: 143 AN: 225014 Hom.: 39 AF XY: 0.000652 AC XY: 79 AN XY: 121242

Gnomad AFR exome AF: 0.0000644

Gnomad AMR exome AF: 0.000212

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000349

Gnomad FIN exome AF: 0.0000526

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.000721 AC: 899 AN: 1246486 Hom.: 261 Cov.: 30 AF XY: 0.000717 AC XY: 446 AN XY: 621698

Gnomad4 AFR exome AF: 0.0000626

Gnomad4 AMR exome AF: 0.000258

Gnomad4 ASJ exome AF: 0.00215

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.000128

Gnomad4 NFE exome AF: 0.000866

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.000550 AC: 72 AN: 130994 Hom.: 24 Cov.: 21 AF XY: 0.000516 AC XY: 33 AN XY: 64010

Gnomad4 AFR AF: 0.0000526

Gnomad4 AMR AF: 0.000664

Gnomad4 ASJ AF: 0.00256

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000115

Gnomad4 NFE AF: 0.000935

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000483 Hom.: 3

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00174 AC: 13

ExAC AF: 0.000700 AC: 79

ClinVar

Significance: risk factor

Submissions summary: Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Anti-D isoimmunization affecting pregnancy Other:1

risk factor, no assertion criteria provided

clinical testing

Australian Red Cross Blood Service

Sep 30, 2014

- -

Hemolytic disease of fetus OR newborn due to RhD isoimmunization Other:1

risk factor, no assertion criteria provided

clinical testing

Australian Red Cross Blood Service

Sep 30, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.10
DANN	Benign	0.97
DEOGEN2	Benign	0.00079	T;.;.;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00047	N
LIST_S2	Benign	0.80	T;T;T;T;T;.
M_CAP	Benign	0.00092	T
MetaRNN	Benign	0.011	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.23	N;.;N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.38	N;.;N;N;N;N
REVEL	Benign	0.030
Sift	Benign	0.75	T;.;T;T;D;D
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.016	B;B;.;.;.;B
Vest4		0.082
MVP		0.11
MPC		0.087
ClinPred		0.0078	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
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: rs146093871; hg19: chr1-25633210; COSMIC: COSV105902313;