NM_016124.6:c.329T>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_016124.6(RHD):c.329T>C(p.Leu110Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,388,154 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00095 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 6 hom. )

Consequence

RHD
NM_016124.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 1.30

Publications

13 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02383706).

BS2

High Homozygotes in GnomAdExome4 at 6 AR 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.329T>C	p.Leu110Pro	missense_variant	Exon 2 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.329T>C	p.Leu110Pro	missense_variant	Exon 2 of 10	1	NM_016124.6	ENSP00000331871.4		Q02161-1

Frequencies

GnomAD3 genomes

AF:

0.000951

AC:

128

AN:

134564

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000206

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000221

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0146

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.00213

GnomAD2 exomes

AF:

0.000902

AC:

203

AN:

225034

AF XY:

0.000981

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000545

Gnomad ASJ exome

AF:

0.000109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000522

Gnomad NFE exome

AF:

0.00166

Gnomad OTH exome

AF:

0.000549

GnomAD4 exome

AF:

0.00151

AC:

1897

AN:

1253478

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

954

AN XY:

625232

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000217

AC:

AN:

32320

American (AMR)

AF:

0.000656

AC:

AN:

42690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23856

East Asian (EAS)

AF:

0.00

AC:

AN:

39554

South Asian (SAS)

AF:

0.000593

AC:

AN:

80920

European-Finnish (FIN)

AF:

0.0000422

AC:

AN:

47378

Middle Eastern (MID)

AF:

0.00246

AC:

AN:

5288

European-Non Finnish (NFE)

AF:

0.00185

AC:

1719

AN:

928038

Other (OTH)

AF:

0.00150

AC:

AN:

53434

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.366

Heterozygous variant carriers

190

286

381

476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000950

AC:

128

AN:

134676

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

AN XY:

66166

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000205

AC:

AN:

38978

American (AMR)

AF:

0.00136

AC:

AN:

13938

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3154

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000221

AC:

AN:

4518

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9216

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

250

European-Non Finnish (NFE)

AF:

0.00162

AC:

AN:

56872

Other (OTH)

AF:

0.00210

AC:

AN:

1902

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.367

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000148

Hom.:

ESP6500AA

AF:

0.000235

AC:

ESP6500EA

AF:

0.00121

AC:

ExAC

AF:

0.00104

AC:

115

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

RhD category D-VII

Pathogenic:1

May 01, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hemolytic disease of fetus and newborn, RH-induced

Uncertain:1

Dec 30, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

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

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.68

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

M_CAP

Benign

0.010

MetaRNN

Benign

0.024

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

MetaSVM

Benign

-0.73

MutationAssessor

Pathogenic

3.0

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

PhyloP100

1.3

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-5.0

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

REVEL

Benign

0.24

Sift

Benign

0.033

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

Sift4G

Uncertain

0.052

T;.;D;D;D;T;D;D;D

Polyphen

1.0

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

Vest4

0.79

MVP

0.41

MPC

0.36

ClinPred

0.14

GERP RS

1.8

Varity_R

0.71

gMVP

0.88

Mutation Taster

=84/16

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_016124.6:c.329T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over