2-38944027-G-A

Variant summary

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

The NM_001145451.5(ARHGEF33):c.917G>A(p.Arg306Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,397,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARHGEF33 NM_001145451.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.52

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=0.16925594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF33	NM_001145451.5	c.917G>A	p.Arg306Lys	missense_variant	10/18	ENST00000409978.7
LOC105374471	XR_939980.3	n.111-7575C>T		intron_variant, non_coding_transcript_variant
ARHGEF33	NM_001367623.3	c.917G>A	p.Arg306Lys	missense_variant	10/19
LOC105374471	XR_001739417.1	n.113-6591C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF33	ENST00000409978.7	c.917G>A	p.Arg306Lys	missense_variant	10/18	5	NM_001145451.5	P1
ARHGEF33	ENST00000698009.1	c.1061G>A	p.Arg354Lys	missense_variant	11/19
ARHGEF33	ENST00000398800.8	c.917G>A	p.Arg306Lys	missense_variant	8/16	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000645 AC: 1 AN: 154958 Hom.: 0 AF XY: 0.0000122 AC XY: 1 AN XY: 82062

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000412

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397692 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000565

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.: 32

Bravo AF: 0.00000378

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

Sep 25, 2023

The c.917G>A (p.R306K) alteration is located in exon 8 (coding exon 8) of the ARHGEF33 gene. This alteration results from a G to A substitution at nucleotide position 917, causing the arginine (R) at amino acid position 306 to be replaced by a lysine (K). 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	-0.10	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.58	N;N
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.49	N;N
REVEL	Benign	0.16
Sift	Benign	0.22	T;T
Sift4G	Benign	0.55	T;T
Vest4		0.27
MutPred		0.54		Loss of helix (P = 0.0123);Loss of helix (P = 0.0123);
MVP		0.25
ClinPred		0.88	D
GERP RS		5.5
gMVP		0.56

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: rs986731308; hg19: chr2-39171168;