1-25301552-T-C

Variant names:

• chr1-25301552-T-C
• NM_016124.6:c.667T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016124.6(RHD):​c.667T>C​(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 1,247,054 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: 3.41

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHD	NM_016124.6	c.667T>C	p.Phe223Leu	missense_variant	Exon 5 of 10	ENST00000328664.9	NP_057208.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHD	ENST00000328664.9	c.667T>C	p.Phe223Leu	missense_variant	Exon 5 of 10	1	NM_016124.6	ENSP00000331871.4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 8.02e-7 AC: 1 AN: 1247054 Hom.: 0 Cov.: 31 AF XY: 0.00000161 AC XY: 1 AN XY: 622014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.76	T;T;T;T;T;T;T;T;.
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.5	M;.;.;M;M;M;.;M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.5	D;.;.;D;D;D;D;D;D
REVEL	Uncertain	0.30
Sift	Benign	0.039	D;.;.;D;D;D;D;D;D
Sift4G	Uncertain	0.035	D;.;D;D;D;D;D;D;D
Polyphen		0.011	B;.;P;.;.;.;.;.;P
Vest4		0.72
MutPred		0.91		Loss of catalytic residue at P221 (P = 0.1859);Loss of catalytic residue at P221 (P = 0.1859);Loss of catalytic residue at P221 (P = 0.1859);Loss of catalytic residue at P221 (P = 0.1859);Loss of catalytic residue at P221 (P = 0.1859);Loss of catalytic residue at P221 (P = 0.1859);Loss of catalytic residue at P221 (P = 0.1859);Loss of catalytic residue at P221 (P = 0.1859);Loss of catalytic residue at P221 (P = 0.1859);
MVP		0.50
MPC		0.13
ClinPred		0.88	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-25628043;