1-25385759-G-A

Position:

• chr1-25385759-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020485.8(RHCE):​c.1025C>T​(p.Thr342Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,613,736 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00074 (6 hom.)
• Consequence: RHCE NM_020485.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.417

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00818634).
• BP6: Variant 1-25385759-G-A is Benign according to our data. Variant chr1-25385759-G-A is described in ClinVar as [Benign]. Clinvar id is 791109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0063 (958/151988) while in subpopulation AFR AF= 0.0196 (814/41446). AF 95% confidence interval is 0.0185. There are 4 homozygotes in gnomad4. There are 484 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHCE	NM_020485.8	c.1025C>T	p.Thr342Ile	missense_variant	7/10	ENST00000294413.13	NP_065231.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHCE	ENST00000294413.13	c.1025C>T	p.Thr342Ile	missense_variant	7/10	1	NM_020485.8	ENSP00000294413.6

Frequencies

GnomAD3 genomes AF: 0.00631 AC: 958 AN: 151870 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00623

Gnomad ASJ AF: 0.00377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00480

GnomAD3 exomes AF: 0.00181 AC: 455 AN: 251450 Hom.: 1 AF XY: 0.00137 AC XY: 186 AN XY: 135896

Gnomad AFR exome AF: 0.0198

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000744 AC: 1088 AN: 1461748 Hom.: 6 Cov.: 31 AF XY: 0.000666 AC XY: 484 AN XY: 727164

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00338

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000185

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00630 AC: 958 AN: 151988 Hom.: 4 Cov.: 31 AF XY: 0.00652 AC XY: 484 AN XY: 74270

Gnomad4 AFR AF: 0.0196

Gnomad4 AMR AF: 0.00622

Gnomad4 ASJ AF: 0.00377

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00475

Alfa AF: 0.00283 Hom.: 0

Bravo AF: 0.00690

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0172 AC: 76

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00212 AC: 257

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 02, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.16
DANN	Benign	0.84
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.61	T;T;T;T;T
MetaRNN	Benign	0.0082	T;T;T;T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Benign	0.0080
Sift	Benign	0.63	T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.0050, 0.027	.;B;.;B;.
Vest4		0.11
MVP		0.14
MPC		0.32
ClinPred		0.0028	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.27

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: rs1053374; hg19: chr1-25712250; COSMIC: COSV99037391;