1-25301049-A-C

Variant summary

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

The NM_016124.6(RHD):c.590A>C(p.Asp197Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000768 in 130,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000077 (0 hom., cov: 21)
• Consequence: RHD NM_016124.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14777234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHD	NM_016124.6	c.590A>C	p.Asp197Ala	missense_variant	4/10	ENST00000328664.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHD	ENST00000328664.9	c.590A>C	p.Asp197Ala	missense_variant	4/10	1	NM_016124.6	P1

Frequencies

GnomAD3 genomes AF: 0.00000768 AC: 1 AN: 130222 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000768 AC: 1 AN: 130222 Hom.: 0 Cov.: 21 AF XY: 0.0000157 AC XY: 1 AN XY: 63658

Gnomad4 AFR AF: 0.0000267

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

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

Jan 17, 2024

The c.590A>C (p.D197A) alteration is located in exon 4 (coding exon 4) of the RHD gene. This alteration results from a A to C substitution at nucleotide position 590, causing the aspartic acid (D) at amino acid position 197 to be replaced by an alanine (A). 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	0.087
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.014	T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.033	N
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;.
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;.;L;L;L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.3	D;.;.;D;D;D;D;D;D
REVEL	Benign	0.019
Sift	Uncertain	0.0080	D;.;.;D;T;D;T;D;T
Sift4G	Uncertain	0.043	D;.;T;T;T;T;T;T;T
Polyphen		0.78	P;.;B;.;.;.;.;.;B
Vest4		0.11
MutPred		0.39		Loss of phosphorylation at T195 (P = 0.0947);Loss of phosphorylation at T195 (P = 0.0947);Loss of phosphorylation at T195 (P = 0.0947);Loss of phosphorylation at T195 (P = 0.0947);Loss of phosphorylation at T195 (P = 0.0947);Loss of phosphorylation at T195 (P = 0.0947);Loss of phosphorylation at T195 (P = 0.0947);Loss of phosphorylation at T195 (P = 0.0947);Loss of phosphorylation at T195 (P = 0.0947);
MVP		0.19
MPC		0.24
ClinPred		0.36	T
GERP RS		1.5
Varity_R		0.14
gMVP		0.34

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: rs1465713698; hg19: chr1-25627540;