4-40243920-CAGA-C

Variant names:

• chr4-40243919-ACAG-AC
• NM_004310.5:c.536_537delGA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004310.5(RHOH):​c.536_537delGA​(p.Arg179LysfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RHOH NM_004310.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.56
• Publications: 0 publications found

Genes affected

RHOH (HGNC:686): (ras homolog family member H) The protein encoded by this gene is a member of the Ras superfamily of guanosine triphosphate (GTP)-metabolizing enzymes. The encoded protein is expressed in hematopoietic cells, where it functions as a negative regulator of cell growth and survival. This gene may be hypermutated or misexpressed in leukemias and lymphomas. Chromosomal translocations in non-Hodgkin's lymphoma occur between this locus and B-cell CLL/lymphoma 6 (BCL6) on chromosome 3, leading to the production of fusion transcripts. Alternative splicing in the 5' untranslated region results in multiple transcript variants that encode the same protein. [provided by RefSeq, May 2013]

RHOH Gene-Disease associations (from GenCC):

• epidermodysplasia verruciformis, susceptibility to, 4

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• epidermodysplasia verruciformis

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• T-cell immunodeficiency with epidermodysplasia verruciformis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004310.5. 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
	RHOH	NM_004310.5	MANE Select	c.536_537delGA	p.Arg179LysfsTer8	frameshift	Exon 3 of 3	NP_004301.1	Q15669
	RHOH	NM_001278359.2		c.536_537delGA	p.Arg179LysfsTer8	frameshift	Exon 4 of 4	NP_001265288.1	Q15669
	RHOH	NM_001278360.2		c.536_537delGA	p.Arg179LysfsTer8	frameshift	Exon 4 of 4	NP_001265289.1	Q15669

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOH	ENST00000381799.10	TSL:1 MANE Select	c.536_537delGA	p.Arg179LysfsTer8	frameshift	Exon 3 of 3	ENSP00000371219.4	Q15669
	RHOH	ENST00000503754.6	TSL:4	c.536_537delGA	p.Arg179LysfsTer8	frameshift	Exon 4 of 4	ENSP00000514769.1	Q15669
	RHOH	ENST00000503941.6	TSL:2	c.536_537delGA	p.Arg179LysfsTer8	frameshift	Exon 3 of 3	ENSP00000426439.2	Q15669

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-40245539;