Genetic Variant NM_016124.6:c.509T>C (chr1-25300968-T-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_016124.6(RHD):c.509T>C(p.Met170Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,378,896 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.00081 ( 18 hom., cov: 21)

Exomes 𝑓: 0.000087 ( 16 hom. )

Consequence

RHD
NM_016124.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.64

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 made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013584554).

BS2

High Homozygotes in GnomAd4 at 18 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 rank	MANE	Protein	UniProt
RHD	NM_016124.6 link	c.509T>C	p.Met170Thr	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.509T>C	p.Met170Thr	missense_variant	Exon 4 of 10	1	NM_016124.6	ENSP00000331871.4		Q02161-1

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

105

AN:

132132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000220

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000549

GnomAD3 exomes

AF:

0.000249

AC:

AN:

224854

Hom.:

AF XY:

0.000116

AC XY:

AN XY:

121138

show subpopulations

Gnomad AFR exome

AF:

0.00328

Gnomad AMR exome

AF:

0.0000303

Gnomad ASJ exome

AF:

0.000109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000209

Gnomad OTH exome

AF:

0.000183

GnomAD4 exome

AF:

0.0000866

AC:

108

AN:

1246646

Hom.:

Cov.:

AF XY:

0.0000643

AC XY:

AN XY:

621768

show subpopulations

Gnomad4 AFR exome

AF:

0.00263

Gnomad4 AMR exome

AF:

0.0000704

Gnomad4 ASJ exome

AF:

0.0000421

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000217

Gnomad4 OTH exome

AF:

0.000320

GnomAD4 genome

AF:

0.000809

AC:

107

AN:

132250

Hom.:

Cov.:

AF XY:

0.000865

AC XY:

AN XY:

64750

show subpopulations

Gnomad4 AFR

AF:

0.00268

Gnomad4 AMR

AF:

0.000219

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000542

ESP6500AA

AF:

0.00496

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000321

AC:

Asia WGS

AF:

0.000296

AC:

AN:

3396

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.19

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

Eigen

Benign

-0.069

Eigen_PC

Benign

-0.099

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.57

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

M_CAP

Benign

0.013

MetaRNN

Benign

0.014

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

MetaSVM

Benign

-0.76

MutationAssessor

Pathogenic

3.4

M;.;.;M;M;M;.;M;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.7

D;.;.;D;D;D;D;D;D

REVEL

Benign

0.27

Sift

Benign

0.044

D;.;.;D;D;D;D;D;D

Sift4G

Benign

0.090

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

Polyphen

0.0030

B;.;D;.;.;.;.;.;D

Vest4

0.59

MVP

0.28

MPC

0.10

ClinPred

0.12

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.72

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over