NM_016124.6:c.671A>G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_016124.6(RHD):c.671A>G(p.Asn224Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000241 in 1,247,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N224T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0000024 ( 1 hom. )

Consequence

RHD
NM_016124.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.75

Publications

1 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

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.671A>G	p.Asn224Ser	missense	Exon 5 of 10	NP_057208.3
RHD	NM_001282871.2		c.671A>G	p.Asn224Ser	missense	Exon 5 of 9	NP_001269800.1	Q02161-4
RHD	NM_001282870.1		c.671A>G	p.Asn224Ser	missense	Exon 5 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.671A>G	p.Asn224Ser	missense	Exon 5 of 10	ENSP00000331871.4	Q02161-1
RHD	ENST00000342055.9	TSL:1	c.671A>G	p.Asn224Ser	missense	Exon 5 of 9	ENSP00000339577.5	Q02161-4
RHD	ENST00000568195.5	TSL:1	c.671A>G	p.Asn224Ser	missense	Exon 5 of 9	ENSP00000456966.1	H3BT10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000444

AC:

AN:

225114

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000644

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000241

AC:

AN:

1247146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

622044

show subpopulations

African (AFR)

AF:

0.0000313

AC:

AN:

31918

American (AMR)

AF:

0.00

AC:

AN:

42636

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23792

East Asian (EAS)

AF:

0.00

AC:

AN:

39540

South Asian (SAS)

AF:

0.00

AC:

AN:

80546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47068

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5256

European-Non Finnish (NFE)

AF:

0.00000217

AC:

AN:

923202

Other (OTH)

AF:

0.00

AC:

AN:

53188

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

Exome Het

Exome Hom

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

Cov.:

ExAC

AF:

0.00000885

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.24

MutationAssessor

Pathogenic

3.6

PhyloP100

5.7

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.75

MutPred

0.98

Gain of disorder (P = 0.065)

MVP

0.74

MPC

0.43

ClinPred

0.99

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.83

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over