2-20447683-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_004040.4(RHOB):c.218C>T(p.Ser73Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RHOB NM_004040.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 7.75

Genes affected

RHOB (HGNC:668): (ras homolog family member B) Predicted to enable GTP binding activity; GTPase activity; and protein kinase binding activity. Involved in several processes, including cellular response to hydrogen peroxide; cellular response to ionizing radiation; and regulation of cell migration. Located in cleavage furrow and endosome membrane. Biomarker of breast cancer. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RHOB
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869
• PP5: Variant 2-20447683-C-T is Pathogenic according to our data. Variant chr2-20447683-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1344805.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHOB	NM_004040.4	c.218C>T	p.Ser73Phe	missense_variant	1/1	ENST00000272233.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHOB	ENST00000272233.6	c.218C>T	p.Ser73Phe	missense_variant	1/1		NM_004040.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

"See Cases" Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Wangler Lab, Baylor College of Medicine

-

This missense RHOB variant at c.218C>T (p.S73F) was seen on exome through the Texome project (R01HG011795). This variant is de novo in the affected patient (PS2), and it was previously reported as a de novo change in two individuals with RHOB-related disorder (PMID:32989326). This variant has not been observed in gnomAD (PM2). Functional studies suggest this variant has a functionally defective gain-of-function mechanism (PS3).This missense variant has an inconclusive CADD score (23.400) and the evolutionary conservation of this residue is high. We predict this variant to be likely pathogenic. -

RHOB-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 25, 2022

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.218C>T (p.S73F) alteration is located in coding exon 1 of the RHOB gene. This alteration results from a C to T substitution at nucleotide position 218, causing the serine (S) at amino acid position 73 to be replaced by a phenylalanine (F). Based on data from the Genome Aggregation Database (gnomAD), the RHOB c.218C>T alteration was not observed, with coverage at this position. This alteration has been described to occur de novo in two unrelated individuals with spastic-dystonic diplegia, expressive language disorder, aortic arch abnormalities, and MRI findings of hyperintense T2 white matter signal (periventricular leukomalacia) (Jin, 2020). The p.S73 amino acid is conserved in available vertebrate species. Biochemical analysis observed protein with the c.218C>T (p.S73F) enhanced GTP hydrolysis and binding as well as accentuated responses to GDP exchange factors (Jin, 2020). The p.S73F alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Recurrent pancreatitis Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Sep 28, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	35
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.065	T
Polyphen		0.87	P
Vest4		0.81
MutPred		0.68		Loss of disorder (P = 0.0245);
MVP		0.81
MPC		2.8
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.93
gMVP		0.96

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: chr2-20647444;