1-25408764-G-A

Variant names:

• chr1-25408764-G-A
• rs57992529
• NM_020485.8:c.254C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_020485.8(RHCE):​c.254C>T​(p.Ala85Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,282,342 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. A85G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000016 (0 hom., cov: 20)
  • Exomes 𝑓: 0.000010 (2 hom.)
• Consequence: RHCE NM_020485.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33324707).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.254C>T	p.Ala85Val	missense	Exon 2 of 10	NP_065231.4	P18577-1
	RHCE	NM_001330430.4		c.254C>T	p.Ala85Val	missense	Exon 2 of 9	NP_001317359.1
	RHCE	NM_138618.6		c.254C>T	p.Ala85Val	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.254C>T	p.Ala85Val	missense	Exon 2 of 10	ENSP00000294413.6	P18577-1
	RHCE	ENST00000413854.5	TSL:1	c.254C>T	p.Ala85Val	missense	Exon 2 of 9	ENSP00000415417.2	E7EU00
	RHCE	ENST00000349438.8	TSL:1	c.254C>T	p.Ala85Val	missense	Exon 2 of 9	ENSP00000334570.5	P18577-2

Frequencies

GnomAD3 genomes AF: 0.0000164 AC: 2 AN: 121748 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000508

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 6 AN: 188504 AF XY: 0.00

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000581

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000420

GnomAD4 exome AF: 0.0000103 AC: 12 AN: 1160594 Hom.: 2 Cov.: 30 AF XY: 0.00000874 AC XY: 5 AN XY: 572120

African (AFR) AF: 0.000152 AC: 5 AN: 32946

American (AMR) AF: 0.00 AC: 0 AN: 32014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19264

East Asian (EAS) AF: 0.00 AC: 0 AN: 21454

South Asian (SAS) AF: 0.0000585 AC: 3 AN: 51308

European-Finnish (FIN) AF: 0.0000465 AC: 2 AN: 43036

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

European-Non Finnish (NFE) AF: 0.00000220 AC: 2 AN: 909070

Other (OTH) AF: 0.00 AC: 0 AN: 47162

GnomAD4 genome AF: 0.0000164 AC: 2 AN: 121748 Hom.: 0 Cov.: 20 AF XY: 0.0000343 AC XY: 2 AN XY: 58250

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

African (AFR) AF: 0.0000508 AC: 2 AN: 39372

American (AMR) AF: 0.00 AC: 0 AN: 11148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2550

East Asian (EAS) AF: 0.00 AC: 0 AN: 2390

South Asian (SAS) AF: 0.00 AC: 0 AN: 2354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53634

Other (OTH) AF: 0.00 AC: 0 AN: 1618

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000309 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.6
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.19
Sift	Benign	0.087	T
Sift4G	Uncertain	0.058	T
Polyphen		0.99	D
Vest4		0.30
MutPred		0.80		Loss of helix (P = 0.1299)
MVP		0.25
MPC		0.33
ClinPred		0.19	T
GERP RS		1.3
gMVP		0.53
Mutation Taster		=94/6	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: rs57992529; hg19: chr1-25735255;