rs200253960

Variant names:

• chr4-40243419-C-A
• rs200253960
• NM_004310.5:c.33C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-40243419-C-A
• chr4-40243419-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_004310.5(RHOH):​c.33C>A​(p.Gly11Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G11G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RHOH NM_004310.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.346
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP7: Synonymous conserved (PhyloP=-0.346 with no splicing effect.

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.33C>A	p.Gly11Gly	synonymous	Exon 3 of 3	NP_004301.1	Q15669
	RHOH	NM_001278359.2		c.33C>A	p.Gly11Gly	synonymous	Exon 4 of 4	NP_001265288.1	Q15669
	RHOH	NM_001278360.2		c.33C>A	p.Gly11Gly	synonymous	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.33C>A	p.Gly11Gly	synonymous	Exon 3 of 3	ENSP00000371219.4	Q15669
	RHOH	ENST00000503754.6	TSL:4	c.33C>A	p.Gly11Gly	synonymous	Exon 4 of 4	ENSP00000514769.1	Q15669
	RHOH	ENST00000503941.6	TSL:2	c.33C>A	p.Gly11Gly	synonymous	Exon 3 of 3	ENSP00000426439.2	Q15669

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452050 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721404

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33204

American (AMR) AF: 0.00 AC: 0 AN: 43504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25424

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.00 AC: 0 AN: 85206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106478

Other (OTH) AF: 0.00 AC: 0 AN: 59838

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.43
DANN	Benign	0.74
PhyloP100		-0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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

Other links and lift over

dbSNP: rs200253960; hg19: chr4-40245039;