rs1053344

Variant names:

• chr1-25408815-T-C
• rs1053344
• NM_020485.8:c.203A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020485.8(RHCE):​c.203A>G​(p.Asn68Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N68D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (1 hom., cov: 20)
  • Exomes 𝑓: 0.000060 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: RHCE NM_020485.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 5 publications found

Genes affected

RHCE (HGNC:10008): (Rh blood group CcEe antigens) 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 both the RhC and RhE antigens on a single polypeptide and a second gene which encodes the RhD protein. 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. A mutation in this gene results in amorph-type Rh-null disease. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Aug 2016]

RHCE Gene-Disease associations (from GenCC):

• Rh deficiency syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03341216).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020485.8. 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
	RHCE	NM_020485.8	MANE Select	c.203A>G	p.Asn68Ser	missense	Exon 2 of 10	NP_065231.4	P18577-1
	RHCE	NM_001330430.4		c.203A>G	p.Asn68Ser	missense	Exon 2 of 9	NP_001317359.1
	RHCE	NM_138618.6		c.203A>G	p.Asn68Ser	missense	Exon 2 of 9	NP_619524.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHCE	ENST00000294413.13	TSL:1 MANE Select	c.203A>G	p.Asn68Ser	missense	Exon 2 of 10	ENSP00000294413.6	P18577-1
	RHCE	ENST00000413854.5	TSL:1	c.203A>G	p.Asn68Ser	missense	Exon 2 of 9	ENSP00000415417.2	E7EU00
	RHCE	ENST00000349438.8	TSL:1	c.203A>G	p.Asn68Ser	missense	Exon 2 of 9	ENSP00000334570.5	P18577-2

Frequencies

GnomAD3 genomes AF: 0.000156 AC: 19 AN: 121430 Hom.: 1 Cov.: 20

Gnomad AFR AF: 0.000254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000901

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: 0.000150

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000370 AC: 7 AN: 189074 AF XY: 0.0000198

Gnomad AFR exome AF: 0.000251

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: 0.0000327

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000603 AC: 70 AN: 1160314 Hom.: 4 Cov.: 30 AF XY: 0.0000577 AC XY: 33 AN XY: 571978

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

African (AFR) AF: 0.000121 AC: 4 AN: 32942

American (AMR) AF: 0.00 AC: 0 AN: 32038

Ashkenazi Jewish (ASJ) AF: 0.0000519 AC: 1 AN: 19282

East Asian (EAS) AF: 0.00 AC: 0 AN: 21452

South Asian (SAS) AF: 0.0000389 AC: 2 AN: 51354

European-Finnish (FIN) AF: 0.0000232 AC: 1 AN: 43036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4340

European-Non Finnish (NFE) AF: 0.0000660 AC: 60 AN: 908706

Other (OTH) AF: 0.0000424 AC: 2 AN: 47164

⚠️ 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: 0.000156 AC: 19 AN: 121430 Hom.: 1 Cov.: 20 AF XY: 0.000138 AC XY: 8 AN XY: 58058

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

African (AFR) AF: 0.000254 AC: 10 AN: 39398

American (AMR) AF: 0.0000901 AC: 1 AN: 11104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2522

East Asian (EAS) AF: 0.00 AC: 0 AN: 2368

South Asian (SAS) AF: 0.00 AC: 0 AN: 2286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 244

European-Non Finnish (NFE) AF: 0.000150 AC: 8 AN: 53430

Other (OTH) AF: 0.00 AC: 0 AN: 1612

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000194594), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000253 Hom.: 0

ExAC AF: 0.000126 AC: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.74
DANN	Benign	0.27
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.95	T
PhyloP100		1.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.90	N
REVEL	Benign	0.043
Sift	Benign	1.0	T
Sift4G	Benign	0.64	T
Polyphen		0.025	B
Vest4		0.14
MVP		0.043
MPC		0.24
ClinPred		0.014	T
GERP RS		1.3
gMVP		0.34
Mutation Taster		=98/2	polymorphism

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: rs1053344; hg19: chr1-25735306;