2-38973731-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001145451.5(ARHGEF33):c.2501A>C(p.Tyr834Ser) 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. 11/17 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: 2.78

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]

SOS1 (HGNC:11187): (SOS Ras/Rac guanine nucleotide exchange factor 1) This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28374967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF33	NM_001145451.5	c.2501A>C	p.Tyr834Ser	missense_variant	18/18	ENST00000409978.7
ARHGEF33	NM_001367623.3	c.*745A>C		3_prime_UTR_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF33	ENST00000409978.7	c.2501A>C	p.Tyr834Ser	missense_variant	18/18	5	NM_001145451.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

May 24, 2023

The c.2501A>C (p.Y834S) alteration is located in exon 16 (coding exon 16) of the ARHGEF33 gene. This alteration results from a A to C substitution at nucleotide position 2501, causing the tyrosine (Y) at amino acid position 834 to be replaced by a serine (S). 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	-0.094	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	22
Dann	Benign	0.96
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.68	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	0.97	N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.90	N;N
REVEL	Benign	0.061
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.37	T;T
Vest4		0.53
MutPred		0.18		Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.30
ClinPred		0.76	D
GERP RS		5.7
gMVP		0.040

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: chr2-39200872;