chr4-40243530-T-C

Variant names:

• chr4-40243530-T-C
• rs76788449
• NM_004310.5:c.144T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.405
• Publications: 3 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOH	NM_004310.5	MANE Select	c.144T>C	p.Asp48Asp	synonymous	Exon 3 of 3	NP_004301.1	Q15669
	RHOH	NM_001278359.2		c.144T>C	p.Asp48Asp	synonymous	Exon 4 of 4	NP_001265288.1	Q15669
	RHOH	NM_001278360.2		c.144T>C	p.Asp48Asp	synonymous	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.144T>C	p.Asp48Asp	synonymous	Exon 3 of 3	ENSP00000371219.4	Q15669
	RHOH	ENST00000503754.6	TSL:4	c.144T>C	p.Asp48Asp	synonymous	Exon 4 of 4	ENSP00000514769.1	Q15669
	RHOH	ENST00000503941.6	TSL:2	c.144T>C	p.Asp48Asp	synonymous	Exon 3 of 3	ENSP00000426439.2	Q15669

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

GnomAD2 exomes AF: 0.00140 AC: 351 AN: 251440 AF XY: 0.00132

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.: 4 Cov.: 31 AF XY: 0.00210 AC XY: 1525 AN XY: 727242

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.00103 AC: 46 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00272 AC: 3022 AN: 1112004

Other (OTH) AF: 0.00151 AC: 91 AN: 60396

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

African (AFR) AF: 0.000506 AC: 21 AN: 41496

American (AMR) AF: 0.000786 AC: 12 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00254 AC: 173 AN: 68002

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epidermodysplasia verruciformis, susceptibility to, 4 (1)
-	-	1	not provided (1)
-	-	1	T-cell immunodeficiency with epidermodysplasia verruciformis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.60
DANN	Benign	0.49
PhyloP100		-0.41
Mutation Taster		=98/2	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: rs76788449; hg19: chr4-40245150; COSMIC: COSV67806034; COSMIC: COSV67806034;