chr1-25385733-T-TATGAAGC

Variant names:

• chr1-25385733-T-TATGAAGC
• rs1553156106
• NM_020485.8:c.1044_1050dupGCTTCAT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_020485.8(RHCE):​c.1044_1050dupGCTTCAT​(p.Thr351AlafsTer52) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RHCE NM_020485.8 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -3.78
• Publications: 0 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-25385733-T-TATGAAGC is Pathogenic according to our data. Variant chr1-25385733-T-TATGAAGC is described in ClinVar as Pathogenic. ClinVar VariationId is 523642.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1044_1050dupGCTTCAT	p.Thr351AlafsTer52	frameshift	Exon 7 of 10	NP_065231.4	P18577-1
	RHCE	NM_001330430.4		c.1044_1050dupGCTTCAT	p.Thr351AlafsTer14	frameshift	Exon 7 of 9	NP_001317359.1
	RHCE	NM_138617.5		c.729_735dupGCTTCAT	p.Thr246AlafsTer14	frameshift	Exon 5 of 7	NP_619523.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHCE	ENST00000294413.13	TSL:1 MANE Select	c.1044_1050dupGCTTCAT	p.Thr351AlafsTer52	frameshift	Exon 7 of 10	ENSP00000294413.6	P18577-1
	RHCE	ENST00000413854.5	TSL:1	c.1044_1050dupGCTTCAT	p.Thr351AlafsTer14	frameshift	Exon 7 of 9	ENSP00000415417.2	E7EU00
	RHCE	ENST00000340849.8	TSL:1	c.729_735dupGCTTCAT	p.Thr246AlafsTer14	frameshift	Exon 5 of 7	ENSP00000345084.4	P18577-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	RH-NULL, AMORPH TYPE (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.8
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553156106; hg19: chr1-25712224;