Genetic Variant NM_016124.6:c.602C>G (chr1-25301061-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_016124.6(RHD):c.602C>G(p.Thr201Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,376,594 control chromosomes in the GnomAD database, including 899 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 0.016 ( 323 hom., cov: 21)

Exomes 𝑓: 0.0022 ( 576 hom. )

Consequence

RHD
NM_016124.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.68

Publications

30 publications found

Variant links:

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]

RHD links:

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

RSRP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024570823).

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHD	NM_016124.6 link	c.602C>G	p.Thr201Arg	missense_variant	Exon 4 of 10	ENST00000328664.9	NP_057208.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHD	ENST00000328664.9 link	c.602C>G	p.Thr201Arg	missense_variant	Exon 4 of 10	1	NM_016124.6	ENSP00000331871.4		Q02161-1

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2002

AN:

130056

Hom.:

319

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00822

Gnomad ASJ

AF:

0.00448

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000694

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0113

Gnomad NFE

AF:

0.000757

Gnomad OTH

AF:

0.0128

GnomAD2 exomes

AF:

0.00469

AC:

1055

AN:

224718

AF XY:

0.00353

show subpopulations

Gnomad AFR exome

AF:

0.0497

Gnomad AMR exome

AF:

0.00445

Gnomad ASJ exome

AF:

0.00370

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000105

Gnomad NFE exome

AF:

0.000734

Gnomad OTH exome

AF:

0.00384

GnomAD4 exome

AF:

0.00219

AC:

2733

AN:

1246420

Hom.:

576

Cov.:

AF XY:

0.00191

AC XY:

1188

AN XY:

621682

show subpopulations

African (AFR)

AF:

0.0538

AC:

1716

AN:

31884

American (AMR)

AF:

0.00493

AC:

210

AN:

42612

Ashkenazi Jewish (ASJ)

AF:

0.00391

AC:

AN:

23776

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39532

South Asian (SAS)

AF:

0.000248

AC:

AN:

80540

European-Finnish (FIN)

AF:

0.0000213

AC:

AN:

47008

Middle Eastern (MID)

AF:

0.00592

AC:

AN:

5068

European-Non Finnish (NFE)

AF:

0.000355

AC:

328

AN:

922838

Other (OTH)

AF:

0.00628

AC:

334

AN:

53162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

112

224

337

449

561

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0155

AC:

2024

AN:

130174

Hom.:

323

Cov.:

AF XY:

0.0144

AC XY:

917

AN XY:

63654

show subpopulations

African (AFR)

AF:

0.0487

AC:

1829

AN:

37542

American (AMR)

AF:

0.00821

AC:

110

AN:

13406

Ashkenazi Jewish (ASJ)

AF:

0.00448

AC:

AN:

3122

East Asian (EAS)

AF:

0.00

AC:

AN:

5080

South Asian (SAS)

AF:

0.000694

AC:

AN:

4320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8508

Middle Eastern (MID)

AF:

0.0123

AC:

AN:

244

European-Non Finnish (NFE)

AF:

0.000757

AC:

AN:

55468

Other (OTH)

AF:

0.0126

AC:

AN:

1822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0114

Hom.:

ESP6500AA

AF:

0.0462

AC:

196

ESP6500EA

AF:

0.00134

AC:

ExAC

AF:

0.00500

AC:

559

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.021

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.016

T;.;.;.;.;.;.;.;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0067

LIST_S2

Benign

0.64

T;T;T;T;T;T;T;T;.

MetaRNN

Benign

0.0025

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

N;.;.;N;N;N;.;N;.

PhyloP100

-1.7

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.3

N;.;.;N;N;N;N;N;N

REVEL

Benign

0.014

Sift

Benign

0.28

T;.;.;T;T;T;T;T;T

Sift4G

Benign

0.14

T;.;T;T;T;T;T;T;T

Polyphen

0.0

B;.;B;.;.;.;.;.;B

Vest4

0.18

MVP

0.030

MPC

0.098

ClinPred

0.0036

GERP RS

-7.9

Varity_R

0.061

gMVP

0.33

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over