Genetic Variant RHD:p.Ser122Ser (chr1-25290671-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_Very_StrongBP7BS2_Supporting

The NM_016124.6(RHD):c.366G>A(p.Ser122Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000326 in 1,378,290 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000046 ( 2 hom., cov: 20)

Exomes 𝑓: 0.000031 ( 12 hom. )

Consequence

RHD
NM_016124.6 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.68

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 1-25290671-G-A is Benign according to our data. Variant chr1-25290671-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 739638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.67 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 2 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.366G>A	p.Ser122Ser	synonymous	Exon 3 of 10	NP_057208.3
RHD	NM_001282871.2		c.366G>A	p.Ser122Ser	synonymous	Exon 3 of 9	NP_001269800.1	Q02161-4
RHD	NM_001282870.1		c.366G>A	p.Ser122Ser	synonymous	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.366G>A	p.Ser122Ser	synonymous	Exon 3 of 10	ENSP00000331871.4	Q02161-1
RHD	ENST00000342055.9	TSL:1	c.366G>A	p.Ser122Ser	synonymous	Exon 3 of 9	ENSP00000339577.5	Q02161-4
RHD	ENST00000568195.5	TSL:1	c.366G>A	p.Ser122Ser	synonymous	Exon 3 of 9	ENSP00000456966.1	H3BT10

Frequencies

GnomAD3 genomes

AF:

0.0000459

AC:

AN:

130736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000261

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000724

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000533

AC:

AN:

224982

AF XY:

0.0000743

show subpopulations

Gnomad AFR exome

AF:

0.0000637

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000419

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000313

AC:

AN:

1247436

Hom.:

Cov.:

AF XY:

0.0000466

AC XY:

AN XY:

622162

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32350

American (AMR)

AF:

0.00

AC:

AN:

42596

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23794

East Asian (EAS)

AF:

0.00

AC:

AN:

39534

South Asian (SAS)

AF:

0.000137

AC:

AN:

80524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47050

Middle Eastern (MID)

AF:

0.000571

AC:

AN:

5254

European-Non Finnish (NFE)

AF:

0.0000238

AC:

AN:

923088

Other (OTH)

AF:

0.0000563

AC:

AN:

53246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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

AF:

0.0000459

AC:

AN:

130854

Hom.:

Cov.:

AF XY:

0.0000469

AC XY:

AN XY:

63940

show subpopulations

African (AFR)

AF:

0.0000260

AC:

AN:

38438

American (AMR)

AF:

0.00

AC:

AN:

13342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3116

East Asian (EAS)

AF:

0.000195

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8674

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000724

AC:

AN:

55250

Other (OTH)

AF:

0.00

AC:

AN:

1812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.37

(source)

DANN

Benign

0.74

PhyloP100

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over