chr2-38943954-A-G

Position:

• chr2-38943954-A-G

Variant summary

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

The NM_001145451.5(ARHGEF33):​c.844A>G​(p.Ile282Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 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: ARHGEF33 NM_001145451.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09

Genes affected

ARHGEF33 (HGNC:37252): (Rho guanine nucleotide exchange factor 33) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. [provided by Alliance of Genome Resources, Apr 2022]

LOC105374471 (HGNC:):

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=0.14570904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF33	NM_001145451.5	c.844A>G	p.Ile282Val	missense_variant	10/18	ENST00000409978.7	NP_001138923.2
LOC105374471	XR_939980.3	n.111-7502T>C		intron_variant, non_coding_transcript_variant
ARHGEF33	NM_001367623.3	c.844A>G	p.Ile282Val	missense_variant	10/19		NP_001354552.1
LOC105374471	XR_001739417.1	n.113-6518T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF33	ENST00000409978.7	c.844A>G	p.Ile282Val	missense_variant	10/18	5	NM_001145451.5	ENSP00000387020	P1
ARHGEF33	ENST00000698009.1	c.988A>G	p.Ile330Val	missense_variant	11/19			ENSP00000513494
ARHGEF33	ENST00000398800.8	c.844A>G	p.Ile282Val	missense_variant	8/16	5		ENSP00000381780	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.844A>G (p.I282V) alteration is located in exon 8 (coding exon 8) of the ARHGEF33 gene. This alteration results from a A to G substitution at nucleotide position 844, causing the isoleucine (I) at amino acid position 282 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	0.98
Eigen	Benign	-0.10
Eigen_PC	Benign	0.091
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.79	.;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N;N
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.14	N;N
REVEL	Benign	0.090
Sift	Benign	0.16	T;T
Sift4G	Benign	0.54	T;T
Vest4		0.20
MutPred		0.40		Gain of MoRF binding (P = 0.0937);Gain of MoRF binding (P = 0.0937);
MVP		0.21
ClinPred		0.36	T
GERP RS		5.5
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs1164517386; hg19: chr2-39171095;