NM_016124.6:c.608C>T

Variant names:

• chr1-25301067-C-T
• rs775528807
• NM_016124.6:c.608C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

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. 13/22 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
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14611313).
• BS2: High Homozygotes in GnomAdExome4 at 9 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016124.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHD	NM_016124.6	MANE Select	c.608C>T	p.Thr203Met	missense	Exon 4 of 10	NP_057208.3
	RHD	NM_001282871.2		c.608C>T	p.Thr203Met	missense	Exon 4 of 9	NP_001269800.1	Q02161-4
	RHD	NM_001282870.1		c.608C>T	p.Thr203Met	missense	Exon 4 of 9	NP_001269799.1	Q5XLT0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHD	ENST00000328664.9	TSL:1 MANE Select	c.608C>T	p.Thr203Met	missense	Exon 4 of 10	ENSP00000331871.4	Q02161-1
	RHD	ENST00000342055.9	TSL:1	c.608C>T	p.Thr203Met	missense	Exon 4 of 9	ENSP00000339577.5	Q02161-4
	RHD	ENST00000568195.5	TSL:1	c.608C>T	p.Thr203Met	missense	Exon 4 of 9	ENSP00000456966.1	H3BT10

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

GnomAD2 exomes AF: 0.0000312 AC: 7 AN: 224686 AF XY: 0.0000165

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 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

African (AFR) AF: 0.00 AC: 0 AN: 31942

American (AMR) AF: 0.0000469 AC: 2 AN: 42610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23768

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39534

South Asian (SAS) AF: 0.0000248 AC: 2 AN: 80530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5018

European-Non Finnish (NFE) AF: 0.0000184 AC: 17 AN: 922772

Other (OTH) AF: 0.0000376 AC: 2 AN: 53154

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

African (AFR) AF: 0.00 AC: 0 AN: 37848

American (AMR) AF: 0.00 AC: 0 AN: 13382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3104

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.0000361 AC: 2 AN: 55474

Other (OTH) AF: 0.00 AC: 0 AN: 1800

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000179 AC: 2

Asia WGS AF: 0.000296 AC: 1 AN: 3390

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.69
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.043
Sift	Benign	0.043	D
Sift4G	Benign	0.17	T
Polyphen		0.96	D
Vest4		0.37
MutPred		0.36		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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

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