1-25390838-T-C

Variant names:

• chr1-25390838-T-C
• rs144163296
• NM_020485.8:c.712A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020485.8(RHCE):​c.712A>G​(p.Met238Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000723 in 1,613,758 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (7 hom.)
• Consequence: RHCE NM_020485.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.968

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]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005721599).
• BP6: Variant 1-25390838-T-C is Benign according to our data. Variant chr1-25390838-T-C is described in ClinVar as [Benign]. Clinvar id is 789917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHCE	NM_020485.8	c.712A>G	p.Met238Val	missense_variant	Exon 5 of 10	ENST00000294413.13	NP_065231.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHCE	ENST00000294413.13	c.712A>G	p.Met238Val	missense_variant	Exon 5 of 10	1	NM_020485.8	ENSP00000294413.6

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152126 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000951 AC: 239 AN: 251336 AF XY: 0.000758

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000460 AC: 673 AN: 1461514 Hom.: 7 Cov.: 31 AF XY: 0.000419 AC XY: 305 AN XY: 727090

Gnomad4 AFR exome AF: 0.0121 AC: 403 AN: 33194

Gnomad4 AMR exome AF: 0.000806 AC: 36 AN: 44692

Gnomad4 ASJ exome AF: 0.0000383 AC: 1 AN: 26136

Gnomad4 EAS exome AF: 0.0000756 AC: 3 AN: 39696

Gnomad4 SAS exome AF: 0.000951 AC: 82 AN: 86248

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.0000647 AC: 72 AN: 1111994

Gnomad4 Remaining exome AF: 0.00119 AC: 72 AN: 60366

GnomAD4 genome AF: 0.00324 AC: 493 AN: 152244 Hom.: 2 Cov.: 32 AF XY: 0.00314 AC XY: 234 AN XY: 74444

Gnomad4 AFR AF: 0.0110 AC: 0.0110409 AN: 0.0110409

Gnomad4 AMR AF: 0.00111 AC: 0.00111082 AN: 0.00111082

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00166 AC: 0.00165837 AN: 0.00165837

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000882 AC: 0.0000881912 AN: 0.0000881912

Gnomad4 OTH AF: 0.00189 AC: 0.00189036 AN: 0.00189036

Alfa AF: 0.000402 Hom.: 0

Bravo AF: 0.00352

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00137 AC: 166

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 24, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.0050
DANN	Benign	0.30
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.42	T;T;T;T
MetaRNN	Benign	0.0057	T;T;T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.8	N;N;N;N
REVEL	Benign	0.057
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;.;B;.
Vest4		0.081
MVP		0.15
MPC		0.30
ClinPred		0.0043	T
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.16
Mutation Taster		=99/1	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

Publications

LitVar

Other links and lift over

dbSNP: rs144163296; hg19: chr1-25717329;