Genetic Variant NM_016124.6:c.541C>T (chr1-25301000-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP7BS2_Supporting

The NM_016124.6(RHD):c.541C>T(p.Leu181Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,378,584 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00052 ( 12 hom., cov: 21)

Exomes 𝑓: 0.000091 ( 22 hom. )

Consequence

RHD
NM_016124.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0100

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_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP7

Synonymous conserved (PhyloP=-0.01 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 12 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.541C>T	p.Leu181Leu	synonymous	Exon 4 of 10	NP_057208.3
RHD	NM_001282871.2		c.541C>T	p.Leu181Leu	synonymous	Exon 4 of 9	NP_001269800.1	Q02161-4
RHD	NM_001282870.1		c.541C>T	p.Leu181Leu	synonymous	Exon 4 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.541C>T	p.Leu181Leu	synonymous	Exon 4 of 10	ENSP00000331871.4	Q02161-1
RHD	ENST00000342055.9	TSL:1	c.541C>T	p.Leu181Leu	synonymous	Exon 4 of 9	ENSP00000339577.5	Q02161-4
RHD	ENST00000568195.5	TSL:1	c.541C>T	p.Leu181Leu	synonymous	Exon 4 of 9	ENSP00000456966.1	H3BT10

Frequencies

GnomAD3 genomes

AF:

0.000524

AC:

AN:

131758

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00165

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000367

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:

0.00

Gnomad OTH

AF:

0.000550

GnomAD2 exomes

AF:

0.000200

AC:

AN:

224836

AF XY:

0.000165

show subpopulations

Gnomad AFR exome

AF:

0.00270

Gnomad AMR exome

AF:

0.0000303

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:

0.0000906

AC:

113

AN:

1246826

Hom.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

621842

show subpopulations

African (AFR)

AF:

0.00285

AC:

AN:

31952

American (AMR)

AF:

0.0000469

AC:

AN:

42616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23788

East Asian (EAS)

AF:

0.00

AC:

AN:

39536

South Asian (SAS)

AF:

0.0000248

AC:

AN:

80552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47032

Middle Eastern (MID)

AF:

0.000190

AC:

AN:

5252

European-Non Finnish (NFE)

AF:

0.00000650

AC:

AN:

922904

Other (OTH)

AF:

0.000207

AC:

AN:

53194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.000524

AC:

AN:

131758

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

64438

show subpopulations

African (AFR)

AF:

0.00165

AC:

AN:

38248

American (AMR)

AF:

0.000367

AC:

AN:

13618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3112

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4326

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

55898

Other (OTH)

AF:

0.000550

AC:

AN:

1818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

3.9

(source)

DANN

Benign

0.78

PhyloP100

-0.010

Mutation Taster

=100/0

polymorphism

(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

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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