RHD p.Phe223Leu

Variant names:

• chr1-25301554-C-A
• NM_016124.6:c.669C>A
• RHD p.Phe223Leu

Your query was ambiguous. Multiple possible variants found:

• chr1-25301554-C-A
• chr1-25301554-C-G
• chr1-25301552-T-C
• chr1-25301552-TTC-CTT
• chr1-25301552-TTC-CTA
• chr1-25301552-TTC-CTG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016124.6(RHD):​c.669C>A​(p.Phe223Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000802 in 1,247,124 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. F223V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: RHD NM_016124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.07
• Publications: 0 publications found

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]

RSRP1 (HGNC:25234): (arginine and serine rich protein 1)

ACMG classification

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, 0.954

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHD	NM_016124.6	MANE Select	c.669C>A	p.Phe223Leu	missense	Exon 5 of 10	NP_057208.3
	RHD	NM_001282871.2		c.669C>A	p.Phe223Leu	missense	Exon 5 of 9	NP_001269800.1	Q02161-4
	RHD	NM_001282870.1		c.669C>A	p.Phe223Leu	missense	Exon 5 of 9	NP_001269799.1	Q5XLT0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHD	ENST00000328664.9	TSL:1 MANE Select	c.669C>A	p.Phe223Leu	missense	Exon 5 of 10	ENSP00000331871.4	Q02161-1
	RHD	ENST00000342055.9	TSL:1	c.669C>A	p.Phe223Leu	missense	Exon 5 of 9	ENSP00000339577.5	Q02161-4
	RHD	ENST00000568195.5	TSL:1	c.669C>A	p.Phe223Leu	missense	Exon 5 of 9	ENSP00000456966.1	H3BT10

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 8.02e-7 AC: 1 AN: 1247124 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 622042

African (AFR) AF: 0.00 AC: 0 AN: 31906

American (AMR) AF: 0.00 AC: 0 AN: 42636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23792

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 80544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47064

Middle Eastern (MID) AF: 0.000190 AC: 1 AN: 5256

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 923204

Other (OTH) AF: 0.00 AC: 0 AN: 53182

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.00050
Eigen_PC	Benign	-0.0097
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		3.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.36
Sift	Benign	0.039	D
Sift4G	Uncertain	0.035	D
Varity_R		0.48
gMVP		0.83
Mutation Taster		=63/37	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-25628045;