4-40197226-G-C

Variant names:

• chr4-40197226-G-C
• rs2245466
• NM_004310.5:c.-405G>C

Variant summary

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

The ENST00000381799.10(RHOH):​c.-405G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 152,126 control chromosomes in the GnomAD database, including 36,481 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 0.69 (36480 hom., cov: 33)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: RHOH ENST00000381799.10 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0330
• Publications: 14 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000381799.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOH	NM_004310.5	MANE Select	c.-405G>C		5_prime_UTR	Exon 1 of 3	NP_004301.1
	RHOH	NM_001278359.2		c.-571G>C		5_prime_UTR	Exon 1 of 4	NP_001265288.1
	RHOH	NM_001278360.2		c.-557G>C		5_prime_UTR	Exon 1 of 4	NP_001265289.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOH	ENST00000381799.10	TSL:1 MANE Select	c.-405G>C		5_prime_UTR	Exon 1 of 3	ENSP00000371219.4
	RHOH	ENST00000514143.1	TSL:3	n.166G>C		non_coding_transcript_exon	Exon 1 of 3
	RHOH	ENST00000514839.1	TSL:4	n.238G>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104955 AN: 152006 Hom.: 36443 Cov.: 33

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.683

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.684

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.657

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 Cov.: 0 AF XY: 1.00 AC XY: 2 AN XY: 2

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) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.691 AC: 105044 AN: 152124 Hom.: 36480 Cov.: 33 AF XY: 0.691 AC XY: 51385 AN XY: 74360

African (AFR) AF: 0.752 AC: 31199 AN: 41466

American (AMR) AF: 0.655 AC: 10008 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 2378 AN: 3470

East Asian (EAS) AF: 0.466 AC: 2415 AN: 5180

South Asian (SAS) AF: 0.731 AC: 3528 AN: 4826

European-Finnish (FIN) AF: 0.684 AC: 7243 AN: 10582

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.678 AC: 46071 AN: 68000

Other (OTH) AF: 0.658 AC: 1389 AN: 2112

Alfa AF: 0.603 Hom.: 1725

Bravo AF: 0.685

Asia WGS AF: 0.633 AC: 2202 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.7
DANN	Benign	0.37
PhyloP100		0.033
PromoterAI		0.21	Neutral
Mutation Taster		=300/0	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: rs2245466; hg19: chr4-40198846;