Genetic Variant RHD:p.Leu181Val (chr1-25301000-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS2_Supporting

The NM_016124.6(RHD):c.541C>G(p.Leu181Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,246,826 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.000014 ( 5 hom. )

Consequence

RHD
NM_016124.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0100

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 Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

BS2

High Homozygotes in GnomAdExome4 at 5 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.541C>G	p.Leu181Val	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.541C>G	p.Leu181Val	missense_variant	Exon 4 of 10	1	NM_016124.6	ENSP00000331871.4		Q02161-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000356

AC:

AN:

224836

Hom.:

AF XY:

0.0000330

AC XY:

AN XY:

121116

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000605

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000628

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000136

AC:

AN:

1246826

Hom.:

Cov.:

AF XY:

0.0000161

AC XY:

AN XY:

621842

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000117

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000130

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000894

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.541C>G (p.L181V) alteration is located in exon 4 (coding exon 4) of the RHD gene. This alteration results from a C to G substitution at nucleotide position 541, causing the leucine (L) at amino acid position 181 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.095

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

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.70

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

M_CAP

Benign

0.013

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.8

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

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.2

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

REVEL

Benign

0.20

Sift

Benign

0.047

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

Sift4G

Benign

0.088

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

Polyphen

0.030

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

Vest4

0.35

MutPred

0.85

Gain of catalytic residue at L181 (P = 0.0178);Gain of catalytic residue at L181 (P = 0.0178);Gain of catalytic residue at L181 (P = 0.0178);Gain of catalytic residue at L181 (P = 0.0178);Gain of catalytic residue at L181 (P = 0.0178);Gain of catalytic residue at L181 (P = 0.0178);Gain of catalytic residue at L181 (P = 0.0178);Gain of catalytic residue at L181 (P = 0.0178);Gain of catalytic residue at L181 (P = 0.0178);

MVP

0.34

MPC

0.13

ClinPred

0.17

GERP RS

0.66

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.090

gMVP

0.65

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over