1-25301067-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_016124.6(RHD):c.608C>T(p.Thr203Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000189 in 1,376,746 control chromosomes in the GnomAD database, including 9 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T203T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 21)
  • Exomes 𝑓: 0.000019 (9 hom.)
• Consequence: RHD NM_016124.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.692

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_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14611313).
• BS2: High Homozygotes in GnomAdExome at 2 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHD	NM_016124.6	c.608C>T	p.Thr203Met	missense_variant	4/10	ENST00000328664.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHD	ENST00000328664.9	c.608C>T	p.Thr203Met	missense_variant	4/10	1	NM_016124.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000153 AC: 2 AN: 130426 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

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: 0.0000361

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000312 AC: 7 AN: 224686 Hom.: 2 AF XY: 0.0000165 AC XY: 2 AN XY: 121068

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000605

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000698

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000210

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000193 AC: 24 AN: 1246320 Hom.: 9 Cov.: 31 AF XY: 0.0000177 AC XY: 11 AN XY: 621618

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000469

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000248

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000184

Gnomad4 OTH exome AF: 0.0000376

GnomAD4 genome AF: 0.0000153 AC: 2 AN: 130426 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 63642

Gnomad4 AFR AF: 0.00

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: 0.0000361

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000179 AC: 2

Asia WGS AF: 0.000296 AC: 1 AN: 3390

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 02, 2024

The c.608C>T (p.T203M) 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 608, causing the threonine (T) at amino acid position 203 to be replaced by a methionine (M). 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	0.089
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	12
Dann	Uncertain	1.0
DEOGEN2	Benign	0.062	T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T;.
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;.;.;M;M;M;.;M;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.9	D;.;.;N;N;D;D;D;D
REVEL	Benign	0.043
Sift	Benign	0.043	D;.;.;D;D;T;T;T;T
Sift4G	Benign	0.17	T;.;T;T;T;T;T;T;T
Polyphen		0.96	D;.;D;.;.;.;.;.;D
Vest4		0.37
MutPred		0.36		Loss of glycosylation at T203 (P = 0.0058);Loss of glycosylation at T203 (P = 0.0058);Loss of glycosylation at T203 (P = 0.0058);Loss of glycosylation at T203 (P = 0.0058);Loss of glycosylation at T203 (P = 0.0058);Loss of glycosylation at T203 (P = 0.0058);Loss of glycosylation at T203 (P = 0.0058);Loss of glycosylation at T203 (P = 0.0058);Loss of glycosylation at T203 (P = 0.0058);
MVP		0.11
MPC		0.31
ClinPred		0.25	T
GERP RS		-0.90
Varity_R		0.032
gMVP		0.34

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: rs775528807; hg19: chr1-25627558; COSMIC: COSV59645451; COSMIC: COSV59645451;