2-38937458-G-C

Variant summary

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

The NM_001145451.5(ARHGEF33):c.689G>C(p.Gly230Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 1,398,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: ARHGEF33 NM_001145451.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

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=0.08519155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF33	NM_001145451.5	c.689G>C	p.Gly230Ala	missense_variant	9/18	ENST00000409978.7
LOC105374471	XR_939980.3	n.111-1006C>G		intron_variant, non_coding_transcript_variant
ARHGEF33	NM_001367623.3	c.689G>C	p.Gly230Ala	missense_variant	9/19
LOC105374471	XR_001739417.1	n.113-22C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF33	ENST00000409978.7	c.689G>C	p.Gly230Ala	missense_variant	9/18	5	NM_001145451.5	P1
ARHGEF33	ENST00000698009.1	c.833G>C	p.Gly278Ala	missense_variant	10/19
ARHGEF33	ENST00000398800.8	c.689G>C	p.Gly230Ala	missense_variant	7/16	5		P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000358 AC: 5 AN: 1398282 Hom.: 0 Cov.: 31 AF XY: 0.00000435 AC XY: 3 AN XY: 689710

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000464

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

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

Oct 12, 2022

The c.689G>C (p.G230A) alteration is located in exon 7 (coding exon 7) of the ARHGEF33 gene. This alteration results from a G to C substitution at nucleotide position 689, causing the glycine (G) at amino acid position 230 to be replaced by an alanine (A). 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	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	19
Dann	Benign	0.97
Eigen	Benign	0.033
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.085	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.92	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.050
Sift	Benign	0.18	T;T
Sift4G	Benign	0.085	T;T
Vest4		0.084
MutPred		0.29		Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);
MVP		0.23
ClinPred		0.45	T
GERP RS		5.6
gMVP		0.21

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: chr2-39164599;