1-25301552-T-G

Variant names:

• chr1-25301552-T-G
• rs1053356
• NM_016124.6:c.667T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016124.6(RHD):​c.667T>G​(p.Phe223Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00734 in 1,378,402 control chromosomes in the GnomAD database, including 2,067 homozygotes. 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 no classification for the single variant (no stars).

• Frequency:
  • Genomes: 𝑓 0.034 (801 hom., cov: 21)
  • Exomes 𝑓: 0.0045 (1266 hom.)
• Consequence: RHD NM_016124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.41
• Publications: 49 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007235974).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

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.667T>G	p.Phe223Val	missense	Exon 5 of 10	NP_057208.3
	RHD	NM_001282871.2		c.667T>G	p.Phe223Val	missense	Exon 5 of 9	NP_001269800.1	Q02161-4
	RHD	NM_001282870.1		c.667T>G	p.Phe223Val	missense	Exon 5 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.667T>G	p.Phe223Val	missense	Exon 5 of 10	ENSP00000331871.4	Q02161-1
	RHD	ENST00000342055.9	TSL:1	c.667T>G	p.Phe223Val	missense	Exon 5 of 9	ENSP00000339577.5	Q02161-4
	RHD	ENST00000568195.5	TSL:1	c.667T>G	p.Phe223Val	missense	Exon 5 of 9	ENSP00000456966.1	H3BT10

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 4427 AN: 131638 Hom.: 796 Cov.: 21

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00446

Gnomad EAS AF: 0.00195

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000226

Gnomad MID AF: 0.0111

Gnomad NFE AF: 0.000986

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.0103 AC: 2328 AN: 225016 AF XY: 0.00847

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00784

Gnomad ASJ exome AF: 0.00370

Gnomad EAS exome AF: 0.00245

Gnomad FIN exome AF: 0.000105

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00622

GnomAD4 exome AF: 0.00454 AC: 5663 AN: 1246646 Hom.: 1266 Cov.: 31 AF XY: 0.00418 AC XY: 2601 AN XY: 621870

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.112 AC: 3523 AN: 31542

American (AMR) AF: 0.00960 AC: 409 AN: 42612

Ashkenazi Jewish (ASJ) AF: 0.00391 AC: 93 AN: 23790

East Asian (EAS) AF: 0.00106 AC: 42 AN: 39538

South Asian (SAS) AF: 0.00344 AC: 277 AN: 80546

European-Finnish (FIN) AF: 0.0000850 AC: 4 AN: 47068

Middle Eastern (MID) AF: 0.0103 AC: 54 AN: 5256

European-Non Finnish (NFE) AF: 0.000698 AC: 644 AN: 923156

Other (OTH) AF: 0.0116 AC: 617 AN: 53138

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0338 AC: 4454 AN: 131756 Hom.: 801 Cov.: 21 AF XY: 0.0315 AC XY: 2030 AN XY: 64500

African (AFR) AF: 0.107 AC: 4062 AN: 38080

American (AMR) AF: 0.0180 AC: 246 AN: 13640

Ashkenazi Jewish (ASJ) AF: 0.00446 AC: 14 AN: 3140

East Asian (EAS) AF: 0.00195 AC: 10 AN: 5116

South Asian (SAS) AF: 0.00183 AC: 8 AN: 4376

European-Finnish (FIN) AF: 0.000226 AC: 2 AN: 8836

Middle Eastern (MID) AF: 0.0121 AC: 3 AN: 248

European-Non Finnish (NFE) AF: 0.000986 AC: 55 AN: 55798

Other (OTH) AF: 0.0293 AC: 54 AN: 1844

Alfa AF: 0.0291 Hom.: 75

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.0905 AC: 384

ESP6500EA AF: 0.00213 AC: 16

ExAC AF: 0.0118 AC: 1331

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.28
Sift	Benign	0.22	T
Sift4G	Uncertain	0.059	T
Polyphen		0.025	B
Vest4		0.58
MPC		0.16
ClinPred		0.076	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.81
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1053356; hg19: chr1-25628043;