4-40243428-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_004310.5(RHOH):c.42T>C(p.Ala14Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000869 in 1,610,418 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000040 ( 1 hom. )

Consequence

RHOH
NM_004310.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -3.54

Publications

0 publications found

Variant links:

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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
epidermodysplasia verruciformis
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
T-cell immunodeficiency with epidermodysplasia verruciformis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RHOH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 4-40243428-T-C is Benign according to our data. Variant chr4-40243428-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 477859.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-3.54 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHOH	NM_004310.5 link	c.42T>C	p.Ala14Ala	synonymous_variant	Exon 3 of 3	ENST00000381799.10	NP_004301.1	Q15669Q6ICP4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHOH	ENST00000381799.10 link	c.42T>C	p.Ala14Ala	synonymous_variant	Exon 3 of 3	1	NM_004310.5	ENSP00000371219.4		Q15669

Frequencies

GnomAD3 genomes

AF:

0.000540

AC:

AN:

151916

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000129

AC:

AN:

248982

AF XY:

0.0000818

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.0000585

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000398

AC:

AN:

1458384

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

725114

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

33364

American (AMR)

AF:

0.0000451

AC:

AN:

44310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25916

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

86036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109864

Other (OTH)

AF:

0.0000498

AC:

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000539

AC:

AN:

152034

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

41470

American (AMR)

AF:

0.0000655

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67962

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000278

Hom.:

Bravo

AF:

0.000604

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

T-cell immunodeficiency with epidermodysplasia verruciformis

Benign:1

Sep 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RHOH-related disorder

Benign:1

Feb 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.3

(source)

DANN

Benign

0.41

PhyloP100

-3.5

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over