NM_004310.5:c.95C>G

Variant names:

• chr4-40243481-C-G
• rs992241762
• NM_004310.5:c.95C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004310.5(RHOH):​c.95C>G​(p.Ala32Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A32V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RHOH NM_004310.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.564
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19712439).

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.95C>G	p.Ala32Gly	missense	Exon 3 of 3	NP_004301.1	Q15669
	RHOH	NM_001278359.2		c.95C>G	p.Ala32Gly	missense	Exon 4 of 4	NP_001265288.1	Q15669
	RHOH	NM_001278360.2		c.95C>G	p.Ala32Gly	missense	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.95C>G	p.Ala32Gly	missense	Exon 3 of 3	ENSP00000371219.4	Q15669
	RHOH	ENST00000503754.6	TSL:4	c.95C>G	p.Ala32Gly	missense	Exon 4 of 4	ENSP00000514769.1	Q15669
	RHOH	ENST00000503941.6	TSL:2	c.95C>G	p.Ala32Gly	missense	Exon 3 of 3	ENSP00000426439.2	Q15669

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.72	N
PhyloP100		0.56
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.23
Sift	Uncertain	0.013	D
Sift4G	Benign	0.062	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.36		Loss of stability (P = 0.0427)
MVP		0.79
MPC		0.83
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.11
gMVP		0.41
Mutation Taster		=85/15	polymorphism

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: rs992241762; hg19: chr4-40245101;