Genetic Variant NM_004310.5:c.144T>C (chr4-40243530-T-C) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_004310.5(RHOH):c.144T>C(p.Asp48Asp) 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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.405

Publications

3 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 -17 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 VariationId 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.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RHOH	NM_004310.5	MANE Select	c.144T>C	p.Asp48Asp	synonymous	Exon 3 of 3	NP_004301.1
RHOH	NM_001278359.2		c.144T>C	p.Asp48Asp	synonymous	Exon 4 of 4	NP_001265288.1
RHOH	NM_001278360.2		c.144T>C	p.Asp48Asp	synonymous	Exon 4 of 4	NP_001265289.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RHOH	ENST00000381799.10	TSL:1 MANE Select	c.144T>C	p.Asp48Asp	synonymous	Exon 3 of 3	ENSP00000371219.4
RHOH	ENST00000503754.6	TSL:4	c.144T>C	p.Asp48Asp	synonymous	Exon 4 of 4	ENSP00000514769.1
RHOH	ENST00000503941.6	TSL:2	c.144T>C	p.Asp48Asp	synonymous	Exon 3 of 3	ENSP00000426439.2

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

214

AN:

151968

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00140

AC:

351

AN:

251440

AF XY:

0.00132

show subpopulations

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 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.:

Cov.:

AF XY:

0.00210

AC XY:

1525

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33480

American (AMR)

AF:

0.00103

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000449

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00272

AC:

3022

AN:

1112004

Other (OTH)

AF:

0.00151

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

200

399

599

798

998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.00141

AC:

214

AN:

152086

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41496

American (AMR)

AF:

0.000786

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00254

AC:

173

AN:

68002

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00189

Hom.:

Bravo

AF:

0.00161

Asia WGS

AF:

0.000289

AC:

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

LINK: link

Submissions by phenotype

T-cell immunodeficiency with epidermodysplasia verruciformis

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RHOH: BP4, BP7

Epidermodysplasia verruciformis, susceptibility to, 4

Benign:1

Oct 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.60

(source)

DANN

Benign

0.49

PhyloP100

-0.41

Mutation Taster

=98/2

polymorphism

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over