chr1-25301618-G-C

Position:

• chr1-25301618-G-C

Variant summary

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

The ENST00000328664.9(RHD):​c.733G>C​(p.Val245Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,380,076 control chromosomes in the GnomAD database, including 410 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 no classification for the single variant (no stars).

• Frequency:
  • Genomes: 𝑓 0.00070 (25 hom., cov: 21)
  • Exomes 𝑓: 0.0011 (385 hom.)
• Consequence: RHD ENST00000328664.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.702

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=0.018821448).
• BS2: High Homozygotes in GnomAd4 at 25 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	Protein	UniProt
RHD	NM_016124.6	c.733G>C	p.Val245Leu	missense_variant	5/10	ENST00000328664.9	NP_057208.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHD	ENST00000328664.9	c.733G>C	p.Val245Leu	missense_variant	5/10	1	NM_016124.6	ENSP00000331871	P1

Frequencies

GnomAD3 genomes AF: 0.000699 AC: 93 AN: 133006 Hom.: 25 Cov.: 21

Gnomad AFR AF: 0.000311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000649

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000683

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00216

GnomAD3 exomes AF: 0.000835 AC: 188 AN: 225230 Hom.: 55 AF XY: 0.000799 AC XY: 97 AN XY: 121358

Gnomad AFR exome AF: 0.000903

Gnomad AMR exome AF: 0.000756

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000157

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.000183

GnomAD4 exome AF: 0.00111 AC: 1387 AN: 1246952 Hom.: 385 Cov.: 30 AF XY: 0.00108 AC XY: 672 AN XY: 621988

Gnomad4 AFR exome AF: 0.000564

Gnomad4 AMR exome AF: 0.000633

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000621

Gnomad4 FIN exome AF: 0.000170

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.000658

GnomAD4 genome AF: 0.000699 AC: 93 AN: 133124 Hom.: 25 Cov.: 21 AF XY: 0.000659 AC XY: 43 AN XY: 65260

Gnomad4 AFR AF: 0.000310

Gnomad4 AMR AF: 0.000648

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000683

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.00214

Alfa AF: 0.000981 Hom.: 3

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000706 AC: 3

ESP6500EA AF: 0.000531 AC: 4

ExAC AF: 0.000928 AC: 105

Asia WGS AF: 0.00148 AC: 5 AN: 3388

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.8
DANN	Benign	0.40
DEOGEN2	Benign	0.018	T;.;.;.;.;.;.;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.54	T;T;T;T;T;T;T;T;.
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.019	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-3.5	N;.;.;N;N;N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	2.4	N;.;.;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;.;.;T;T;T;T;T;T
Sift4G	Benign	1.0	T;.;T;T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;.;.;.;.;B
Vest4		0.054
MutPred		0.72		Loss of catalytic residue at V245 (P = 0.0645);Loss of catalytic residue at V245 (P = 0.0645);Loss of catalytic residue at V245 (P = 0.0645);Loss of catalytic residue at V245 (P = 0.0645);Loss of catalytic residue at V245 (P = 0.0645);Loss of catalytic residue at V245 (P = 0.0645);Loss of catalytic residue at V245 (P = 0.0645);Loss of catalytic residue at V245 (P = 0.0645);Loss of catalytic residue at V245 (P = 0.0645);
MVP		0.055
MPC		0.084
ClinPred		0.015	T
GERP RS		0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.040
gMVP		0.26

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: rs150073306; hg19: chr1-25628109;