4-40243415-T-C

Position:

• chr4-40243415-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004310.5(RHOH):​c.29T>C​(p.Val10Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RHOH NM_004310.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHOH	NM_004310.5	c.29T>C	p.Val10Ala	missense_variant	3/3	ENST00000381799.10	NP_004301.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHOH	ENST00000381799.10	c.29T>C	p.Val10Ala	missense_variant	3/3	1	NM_004310.5	ENSP00000371219.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

T-cell immunodeficiency with epidermodysplasia verruciformis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 10 of the RHOH protein (p.Val10Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RHOH-related conditions. ClinVar contains an entry for this variant (Variation ID: 1517425). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;D;D;.;D;D;D;D;D;D;D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	.;D;.;.;.;.;D;.;.;.;.;T;.
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.5	M;.;M;M;.;M;.;M;M;M;M;M;M
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.4	D;D;.;.;D;.;D;.;.;.;.;.;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;.;.;.;.;D;.;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;.;D;D;D;D;D;D;D;D
Polyphen		0.99	D;.;D;D;.;D;.;D;D;D;D;D;D
Vest4		0.93
MutPred		0.81		Loss of stability (P = 0.0179);Loss of stability (P = 0.0179);Loss of stability (P = 0.0179);Loss of stability (P = 0.0179);Loss of stability (P = 0.0179);Loss of stability (P = 0.0179);Loss of stability (P = 0.0179);Loss of stability (P = 0.0179);Loss of stability (P = 0.0179);Loss of stability (P = 0.0179);Loss of stability (P = 0.0179);Loss of stability (P = 0.0179);Loss of stability (P = 0.0179);
MVP		0.93
MPC		2.1
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.63
gMVP		0.91

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-40245035;