chr4-40212934-A-G

Variant names:

• chr4-40212934-A-G
• rs2280307
• NM_004310.5:c.-331+15634A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004310.5(RHOH):​c.-331+15634A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.663 in 152,126 control chromosomes in the GnomAD database, including 33,669 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.66 (33666 hom., cov: 32)
  • Exomes 𝑓: 0.88 (3 hom.)
• Consequence: RHOH NM_004310.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

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.-331+15634A>G		intron	N/A	NP_004301.1	Q15669
	RHOH	NM_001278359.2		c.-497+15634A>G		intron	N/A	NP_001265288.1	Q15669
	RHOH	NM_001278360.2		c.-482-5213A>G		intron	N/A	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.-331+15634A>G		intron	N/A	ENSP00000371219.4	Q15669
	RHOH	ENST00000503754.6	TSL:4	c.-331+15634A>G		intron	N/A	ENSP00000514769.1	Q15669
	RHOH	ENST00000503941.6	TSL:2	c.-331+19122A>G		intron	N/A	ENSP00000426439.2	Q15669

Frequencies

GnomAD3 genomes AF: 0.663 AC: 100789 AN: 152004 Hom.: 33623 Cov.: 32

Gnomad AFR AF: 0.623

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.711

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.667

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.761

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.659

GnomAD4 exome AF: 0.875 AC: 7 AN: 8 Hom.: 3 AF XY: 0.875 AC XY: 7 AN XY: 8

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.875 AC: 7 AN: 8

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.663 AC: 100886 AN: 152118 Hom.: 33666 Cov.: 32 AF XY: 0.666 AC XY: 49559 AN XY: 74364

African (AFR) AF: 0.623 AC: 25854 AN: 41514

American (AMR) AF: 0.712 AC: 10882 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 2373 AN: 3468

East Asian (EAS) AF: 0.666 AC: 3445 AN: 5172

South Asian (SAS) AF: 0.566 AC: 2720 AN: 4806

European-Finnish (FIN) AF: 0.761 AC: 8055 AN: 10586

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.668 AC: 45414 AN: 67972

Other (OTH) AF: 0.658 AC: 1386 AN: 2106

Alfa AF: 0.680 Hom.: 12875

Bravo AF: 0.659

Asia WGS AF: 0.561 AC: 1951 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0070
DANN	Benign	0.21
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs2280307; hg19: chr4-40214554;