rs121912762

chr1-25284753-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BP4

The NM_016124.6(RHD):c.329T>C(p.Leu110Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,388,154 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.00095 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: RHD NM_016124.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.30

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 Uncertain_significance. Variant got 0 ACMG points.

• PP5: Variant 1-25284753-T-C is Pathogenic according to our data. Variant chr1-25284753-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 17712.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-25284753-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.02383706).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHD	NM_016124.6	c.329T>C	p.Leu110Pro	missense_variant	2/10	ENST00000328664.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHD	ENST00000328664.9	c.329T>C	p.Leu110Pro	missense_variant	2/10	1	NM_016124.6	P1

Frequencies

GnomAD3 genomes AF: 0.000951 AC: 128 AN: 134564 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000221

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0146

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.00213

GnomAD3 exomes AF: 0.000902 AC: 203 AN: 225034 Hom.: 1 AF XY: 0.000981 AC XY: 119 AN XY: 121264

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000545

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000662

Gnomad FIN exome AF: 0.0000522

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.000549

GnomAD4 exome AF: 0.00151 AC: 1897 AN: 1253478 Hom.: 6 Cov.: 34 AF XY: 0.00153 AC XY: 954 AN XY: 625232

Gnomad4 AFR exome AF: 0.000217

Gnomad4 AMR exome AF: 0.000656

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000593

Gnomad4 FIN exome AF: 0.0000422

Gnomad4 NFE exome AF: 0.00185

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.000950 AC: 128 AN: 134676 Hom.: 1 Cov.: 32 AF XY: 0.00104 AC XY: 69 AN XY: 66166

Gnomad4 AFR AF: 0.000205

Gnomad4 AMR AF: 0.00136

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000221

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00162

Gnomad4 OTH AF: 0.00210

Alfa AF: 0.000845 Hom.: 0

ESP6500AA AF: 0.000235 AC: 1

ESP6500EA AF: 0.00121 AC: 9

ExAC AF: 0.00104 AC: 115

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

RhD category D-VII Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.021	T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.68	T;T;T;T;T;T;T;T;.
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.024	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Pathogenic	3.0	M;.;.;M;M;M;.;M;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.0	D;.;.;D;D;D;D;D;D
REVEL	Benign	0.24
Sift	Benign	0.033	D;.;.;D;D;D;D;D;D
Sift4G	Uncertain	0.052	T;.;D;D;D;T;D;D;D
Polyphen		1.0	D;.;B;.;.;.;.;.;B
Vest4		0.79
MVP		0.41
MPC		0.36
ClinPred		0.14	T
GERP RS		1.8
Varity_R		0.71
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs121912762; hg19: chr1-25611244;