4-40243481-C-T

Position:

• chr4-40243481-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004310.5(RHOH):​c.95C>T​(p.Ala32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RHOH NM_004310.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.564

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19304481).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHOH	NM_004310.5	c.95C>T	p.Ala32Val	missense_variant	3/3	ENST00000381799.10	NP_004301.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHOH	ENST00000381799.10	c.95C>T	p.Ala32Val	missense_variant	3/3	1	NM_004310.5	ENSP00000371219.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;T;T;T;T;T;T;T;T;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.96	.;D;.;.;.;D;.;.;.;.;T;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.78	N;.;N;N;N;.;N;N;N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.60	N;N;.;.;.;N;.;.;.;.;.;N
REVEL	Benign	0.23
Sift	Benign	0.21	T;T;.;.;.;T;.;.;.;.;.;T
Sift4G	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;B;B;B;.;B;B;B;B;B;B
Vest4		0.15
MutPred		0.34		Loss of disorder (P = 0.0778);Loss of disorder (P = 0.0778);Loss of disorder (P = 0.0778);Loss of disorder (P = 0.0778);Loss of disorder (P = 0.0778);Loss of disorder (P = 0.0778);Loss of disorder (P = 0.0778);Loss of disorder (P = 0.0778);Loss of disorder (P = 0.0778);Loss of disorder (P = 0.0778);Loss of disorder (P = 0.0778);Loss of disorder (P = 0.0778);
MVP		0.81
MPC		0.82
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.050
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-40245101;