chr1-25290761-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_016124.6(RHD):c.456C>G(p.Asn152Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000225 in 1,376,678 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N152T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000023 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000022 ( 4 hom. )

Consequence

RHD
NM_016124.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0290

Publications

0 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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07377821).

BS2

High Homozygotes in GnomAdExome4 at 4 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016124.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RHD	NM_016124.6	MANE Select	c.456C>G	p.Asn152Lys	missense	Exon 3 of 10	NP_057208.3
RHD	NM_001282871.2		c.456C>G	p.Asn152Lys	missense	Exon 3 of 9	NP_001269800.1	Q02161-4
RHD	NM_001282870.1		c.456C>G	p.Asn152Lys	missense	Exon 3 of 9	NP_001269799.1	Q5XLT0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RHD	ENST00000328664.9	TSL:1 MANE Select	c.456C>G	p.Asn152Lys	missense	Exon 3 of 10	ENSP00000331871.4	Q02161-1
RHD	ENST00000342055.9	TSL:1	c.456C>G	p.Asn152Lys	missense	Exon 3 of 9	ENSP00000339577.5	Q02161-4
RHD	ENST00000568195.5	TSL:1	c.456C>G	p.Asn152Lys	missense	Exon 3 of 9	ENSP00000456966.1	H3BT10

Frequencies

GnomAD3 genomes

AF:

0.0000232

AC:

AN:

129158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000548

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000533

AC:

AN:

225094

AF XY:

0.0000412

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000314

Gnomad NFE exome

AF:

0.0000628

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000224

AC:

AN:

1247520

Hom.:

Cov.:

AF XY:

0.0000225

AC XY:

AN XY:

622188

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32190

American (AMR)

AF:

0.00

AC:

AN:

42614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23786

East Asian (EAS)

AF:

0.00

AC:

AN:

39534

South Asian (SAS)

AF:

0.00

AC:

AN:

80532

European-Finnish (FIN)

AF:

0.000383

AC:

AN:

47042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5256

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

923336

Other (OTH)

AF:

0.00

AC:

AN:

53230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000232

AC:

AN:

129158

Hom.:

Cov.:

AF XY:

0.0000318

AC XY:

AN XY:

62974

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

37794

American (AMR)

AF:

0.00

AC:

AN:

13182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3116

East Asian (EAS)

AF:

0.00

AC:

AN:

5092

South Asian (SAS)

AF:

0.00

AC:

AN:

4130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

262

European-Non Finnish (NFE)

AF:

0.0000548

AC:

AN:

54730

Other (OTH)

AF:

0.00

AC:

AN:

1750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ExAC

AF:

0.0000622

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.75

CADD

Benign

6.4

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.0017

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.024

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0024

MetaRNN

Benign

0.074

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.029

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.38

REVEL

Benign

0.018

Sift

Benign

0.057

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.13

MutPred

0.38

Gain of ubiquitination at N152 (P = 0.0289)

MVP

0.24

MPC

0.099

ClinPred

0.027

GERP RS

0.77

Varity_R

0.070

gMVP

0.35

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over