1-25284694-G-C

Variant names:

• chr1-25284694-G-C
• rs1248638537
• NM_016124.6:c.270G>C

Variant summary

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

The NM_016124.6(RHD):​c.270G>C​(p.Trp90Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000399 in 1,254,368 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Affects (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: RHD NM_016124.6 missense
• Clinical Significance: Affects no assertion criteria provided O:1
• Conservation: PhyloP100: 1.73

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHD	NM_016124.6	c.270G>C	p.Trp90Cys	missense_variant	Exon 2 of 10	ENST00000328664.9	NP_057208.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHD	ENST00000328664.9	c.270G>C	p.Trp90Cys	missense_variant	Exon 2 of 10	1	NM_016124.6	ENSP00000331871.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000443 AC: 1 AN: 225724 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 121644

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000399 AC: 5 AN: 1254368 Hom.: 0 Cov.: 34 AF XY: 0.00000320 AC XY: 2 AN XY: 625678

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: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000431

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Affects

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Weakened expression of D antigen Other:1

Jan 14, 2019

Australian Red Cross Blood Service

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: research

We have identified c.270G>C in three samples to date. All show reduced expression of the RhD antigen by serology. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.056	T;.;.;.;.;.;.;.;.
Eigen	Benign	0.086
Eigen_PC	Benign	-0.057
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;.
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.8	M;.;.;M;M;M;.;M;.
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-7.9	D;.;.;D;D;D;D;D;D
REVEL	Benign	0.15
Sift	Benign	0.092	T;.;.;D;D;D;D;D;D
Sift4G	Benign	0.093	T;.;D;D;D;D;D;D;D
Polyphen		0.40	B;.;D;.;.;.;.;.;D
Vest4		0.49
MutPred		0.62		Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);
MVP		0.37
MPC		0.59
ClinPred		0.90	D
GERP RS		1.9
Varity_R		0.51
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1248638537; hg19: chr1-25611185;