1-25408764-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020485.8(RHCE):​c.254C>G​(p.Ala85Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 1,282,438 control chromosomes in the GnomAD database, including 717 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (293 hom., cov: 20)
  • Exomes 𝑓: 0.0022 (424 hom.)
• Consequence: RHCE NM_020485.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009218127).
• BP6: Variant 1-25408764-G-C is Benign according to our data. Variant chr1-25408764-G-C is described in ClinVar as Benign. ClinVar VariationId is 775525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

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>G	p.Ala85Gly	missense	Exon 2 of 10	NP_065231.4	P18577-1
	RHCE	NM_001330430.4		c.254C>G	p.Ala85Gly	missense	Exon 2 of 9	NP_001317359.1
	RHCE	NM_138618.6		c.254C>G	p.Ala85Gly	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>G	p.Ala85Gly	missense	Exon 2 of 10	ENSP00000294413.6	P18577-1
	RHCE	ENST00000413854.5	TSL:1	c.254C>G	p.Ala85Gly	missense	Exon 2 of 9	ENSP00000415417.2	E7EU00
	RHCE	ENST00000349438.8	TSL:1	c.254C>G	p.Ala85Gly	missense	Exon 2 of 9	ENSP00000334570.5	P18577-2

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2234 AN: 121744 Hom.: 293 Cov.: 20

Gnomad AFR AF: 0.0521

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00806

Gnomad NFE AF: 0.000690

Gnomad OTH AF: 0.0173

GnomAD2 exomes AF: 0.00556 AC: 1049 AN: 188504 AF XY: 0.00438

Gnomad AFR exome AF: 0.0558

Gnomad AMR exome AF: 0.00507

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000263

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00217 AC: 2520 AN: 1160594 Hom.: 424 Cov.: 30 AF XY: 0.00193 AC XY: 1107 AN XY: 572120

African (AFR) AF: 0.0566 AC: 1865 AN: 32946

American (AMR) AF: 0.00587 AC: 188 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: 0.000117 AC: 6 AN: 51308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43036

Middle Eastern (MID) AF: 0.00369 AC: 16 AN: 4340

European-Non Finnish (NFE) AF: 0.000234 AC: 213 AN: 909070

Other (OTH) AF: 0.00492 AC: 232 AN: 47162

GnomAD4 genome AF: 0.0183 AC: 2231 AN: 121844 Hom.: 293 Cov.: 20 AF XY: 0.0173 AC XY: 1007 AN XY: 58360

African (AFR) AF: 0.0518 AC: 2047 AN: 39494

American (AMR) AF: 0.0105 AC: 117 AN: 11150

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 2384

South Asian (SAS) AF: 0.00 AC: 0 AN: 2348

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

Middle Eastern (MID) AF: 0.00855 AC: 2 AN: 234

European-Non Finnish (NFE) AF: 0.000690 AC: 37 AN: 53628

Other (OTH) AF: 0.0173 AC: 28 AN: 1622

Alfa AF: 0.000753 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0493 AC: 214

ESP6500EA AF: 0.000685 AC: 5

ExAC AF: 0.00594 AC: 576

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.6
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.49
MVP		0.33
MPC		0.72
ClinPred		0.059	T
GERP RS		1.3
gMVP		0.54
Mutation Taster		=100/0	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: rs57992529; hg19: chr1-25735255; COSMIC: COSV99037400;