rs76788449

chr4-40243530-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_004310.5(RHOH):c.144T>C(p.Asp48=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,613,972 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (4 hom.)
• Consequence: RHOH NM_004310.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.405

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 4-40243530-T-C is Benign according to our data. Variant chr4-40243530-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 477858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.405 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHOH	NM_004310.5	c.144T>C	p.Asp48=	synonymous_variant	3/3	ENST00000381799.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHOH	ENST00000381799.10	c.144T>C	p.Asp48=	synonymous_variant	3/3	1	NM_004310.5	P1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 151968 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000508

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00140 AC: 351 AN: 251440 Hom.: 1 AF XY: 0.00132 AC XY: 179 AN XY: 135894

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00251

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00219 AC: 3201 AN: 1461886 Hom.: 4 Cov.: 31 AF XY: 0.00210 AC XY: 1525 AN XY: 727242

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00272

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152086 Hom.: 0 Cov.: 31 AF XY: 0.00132 AC XY: 98 AN XY: 74338

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00254

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00189 Hom.: 1

Bravo AF: 0.00161

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00249

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

T-cell immunodeficiency with epidermodysplasia verruciformis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

RHOH: BP4, BP7 -

Epidermodysplasia verruciformis, susceptibility to, 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.60
Dann	Benign	0.49

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

LitVar

Other links and lift over

dbSNP: rs76788449; hg19: chr4-40245150; COSMIC: COSV67806034; COSMIC: COSV67806034;