NM_016124.6:c.270G>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.270G>C	p.Trp90Cys	missense	Exon 2 of 10	NP_057208.3
	RHD	NM_001282871.2		c.270G>C	p.Trp90Cys	missense	Exon 2 of 9	NP_001269800.1	Q02161-4
	RHD	NM_001282870.1		c.270G>C	p.Trp90Cys	missense	Exon 2 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.270G>C	p.Trp90Cys	missense	Exon 2 of 10	ENSP00000331871.4	Q02161-1
	RHD	ENST00000342055.9	TSL:1	c.270G>C	p.Trp90Cys	missense	Exon 2 of 9	ENSP00000339577.5	Q02161-4
	RHD	ENST00000568195.5	TSL:1	c.270G>C	p.Trp90Cys	missense	Exon 2 of 9	ENSP00000456966.1	H3BT10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000443 AC: 1 AN: 225724 AF XY: 0.00

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 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

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

African (AFR) AF: 0.00 AC: 0 AN: 32366

American (AMR) AF: 0.00 AC: 0 AN: 42726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5296

European-Non Finnish (NFE) AF: 0.00000431 AC: 4 AN: 928710

Other (OTH) AF: 0.00 AC: 0 AN: 53484

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00384931), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Affects

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Weakened expression of D antigen (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.7
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Benign	0.15
Sift	Benign	0.092	T
Sift4G	Benign	0.093	T
Polyphen		0.40	B
Vest4		0.49
MutPred		0.62		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
Mutation Taster		=76/24	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: rs1248638537; hg19: chr1-25611185;