chr2-46581025-A-G

Variant names:

• chr2-46581025-A-G
• NM_012249.4:c.560A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012249.4(RHOQ):​c.560A>G​(p.Lys187Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHOQ NM_012249.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76
• Publications: 0 publications found

Genes affected

RHOQ (HGNC:17736): (ras homolog family member Q) This gene encodes a member of the Rho family of small GTPases, which cycle between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape, attachment, and motility. The encoded protein is an important signalling protein for sarcomere assembly and has been shown to play a significant role in the exocytosis of the solute carrier family 2, facilitated glucose transporter member 4 and other proteins, possibly acting as the signal that turns on the membrane fusion machinery. Three related pseudogene have been identified on chromosomes 2 and 14. [provided by RefSeq, Aug 2011]

PIGF (HGNC:8962): (phosphatidylinositol glycan anchor biosynthesis class F) This gene encodes a protein involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor, a glycolipid containing three mannose molecules in its core backbone, is found on many blood cells where it serves to anchor proteins to the cell surface. The encoded protein and another GPI synthesis protein, PIGO, function in the transfer of ethanolaminephosphate to the third mannose in GPI. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

PIGF Gene-Disease associations (from GenCC):

• onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13747543).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012249.4. 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
	RHOQ	NM_012249.4	MANE Select	c.560A>G	p.Lys187Arg	missense	Exon 5 of 5	NP_036381.2	P17081
	PIGF	NM_002643.4	MANE Select	c.*453T>C		3_prime_UTR	Exon 6 of 6	NP_002634.1	Q6IB04
	PIGF	NM_173074.3		c.*597T>C		3_prime_UTR	Exon 7 of 7	NP_775097.1	Q07326-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOQ	ENST00000238738.9	TSL:1 MANE Select	c.560A>G	p.Lys187Arg	missense	Exon 5 of 5	ENSP00000238738.4	P17081
	PIGF	ENST00000281382.11	TSL:1 MANE Select	c.*453T>C		3_prime_UTR	Exon 6 of 6	ENSP00000281382.6	Q07326-1
	RHOQ	ENST00000945010.1		c.422A>G	p.Lys141Arg	missense	Exon 4 of 4	ENSP00000615069.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.082
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.084
Sift	Benign	0.34	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.38		Loss of methylation at K187 (P = 0.0275)
MVP		0.70
MPC		0.60
ClinPred		0.66	D
GERP RS		4.6
Varity_R		0.18
gMVP		0.55
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr2-46808164;