chr1-25301028-C-T

Position:

• chr1-25301028-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016124.6(RHD):​c.569C>T​(p.Pro190Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000016 in 1,246,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: RHD NM_016124.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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 (HGNC:):

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21157095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHD	NM_016124.6	c.569C>T	p.Pro190Leu	missense_variant	4/10	ENST00000328664.9	NP_057208.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHD	ENST00000328664.9	c.569C>T	p.Pro190Leu	missense_variant	4/10	1	NM_016124.6	ENSP00000331871.4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000160 AC: 2 AN: 1246834 Hom.: 0 Cov.: 31 AF XY: 0.00000161 AC XY: 1 AN XY: 621850

Gnomad4 AFR exome AF: 0.0000627

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2024

The c.569C>T (p.P190L) alteration is located in exon 4 (coding exon 4) of the RHD gene. This alteration results from a C to T substitution at nucleotide position 569, causing the proline (P) at amino acid position 190 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.040	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.2	M;.;.;M;M;M;.;M;.
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-5.2	D;.;.;D;D;D;D;D;D
REVEL	Benign	0.056
Sift	Uncertain	0.0040	D;.;.;D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;.;D;D;D;D;D;D;D
Polyphen		0.99	D;.;P;.;.;.;.;.;P
Vest4		0.28
MutPred		0.47		Loss of disorder (P = 0.0284);Loss of disorder (P = 0.0284);Loss of disorder (P = 0.0284);Loss of disorder (P = 0.0284);Loss of disorder (P = 0.0284);Loss of disorder (P = 0.0284);Loss of disorder (P = 0.0284);Loss of disorder (P = 0.0284);Loss of disorder (P = 0.0284);
MVP		0.44
MPC		0.42
ClinPred		0.94	D
GERP RS		2.8
Varity_R		0.096
gMVP		0.37

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: rs1643347472; hg19: chr1-25627519;