1-25402721-T-A

Position:

• chr1-25402721-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_020485.8(RHCE):​c.361A>T​(p.Met121Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,988 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0011 (20 hom.)
• Consequence: RHCE NM_020485.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.499

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013885826).
• BP6: Variant 1-25402721-T-A is Benign according to our data. Variant chr1-25402721-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 2638499.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 20 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHCE	NM_020485.8	c.361A>T	p.Met121Leu	missense_variant	3/10	ENST00000294413.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHCE	ENST00000294413.13	c.361A>T	p.Met121Leu	missense_variant	3/10	1	NM_020485.8	P1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152004 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.00520

Gnomad FIN AF: 0.00576

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00179 AC: 449 AN: 251466 Hom.: 3 AF XY: 0.00195 AC XY: 265 AN XY: 135910

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00674

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.00684

Gnomad NFE exome AF: 0.000598

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00106 AC: 1551 AN: 1461866 Hom.: 20 Cov.: 32 AF XY: 0.00114 AC XY: 827 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0154

Gnomad4 SAS exome AF: 0.00264

Gnomad4 FIN exome AF: 0.00560

Gnomad4 NFE exome AF: 0.000281

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152122 Hom.: 0 Cov.: 30 AF XY: 0.00144 AC XY: 107 AN XY: 74372

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0104

Gnomad4 SAS AF: 0.00521

Gnomad4 FIN AF: 0.00576

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000569 Hom.: 0

Bravo AF: 0.000412

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00190 AC: 231

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

RHCE: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.6
DANN	Benign	0.51
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.55	T;T;T;T;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.014	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N
REVEL	Benign	0.036
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	0.45	T;T;T;T;T;T
Polyphen		0.0020, 0.0040, 0.0	.;B;.;B;B;.
Vest4		0.18
MutPred		0.58		Loss of catalytic residue at I125 (P = 0.1977);Loss of catalytic residue at I125 (P = 0.1977);.;Loss of catalytic residue at I125 (P = 0.1977);Loss of catalytic residue at I125 (P = 0.1977);Loss of catalytic residue at I125 (P = 0.1977);
MVP		0.27
MPC		0.28
ClinPred		0.019	T
GERP RS		0.53
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1053345; hg19: chr1-25729212; COSMIC: COSV53802308; COSMIC: COSV53802308;