2-38937487-G-C

Variant summary

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

The NM_001145451.5(ARHGEF33):c.718G>C(p.Asp240His) variant causes a missense change. The variant allele was found at a frequency of 0.00000214 in 1,399,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ARHGEF33 NM_001145451.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.50

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27157468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF33	NM_001145451.5	c.718G>C	p.Asp240His	missense_variant	9/18	ENST00000409978.7
LOC105374471	XR_939980.3	n.111-1035C>G		intron_variant, non_coding_transcript_variant
ARHGEF33	NM_001367623.3	c.718G>C	p.Asp240His	missense_variant	9/19
LOC105374471	XR_001739417.1	n.113-51C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF33	ENST00000409978.7	c.718G>C	p.Asp240His	missense_variant	9/18	5	NM_001145451.5	P1
ARHGEF33	ENST00000698009.1	c.862G>C	p.Asp288His	missense_variant	10/19
ARHGEF33	ENST00000398800.8	c.718G>C	p.Asp240His	missense_variant	7/16	5		P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.0000128 AC: 2 AN: 156314 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 82842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000878

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399036 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690036

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: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000172

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

Feb 11, 2022

The c.718G>C (p.D240H) 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 718, causing the aspartic acid (D) at amino acid position 240 to be replaced by a histidine (H). 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	-0.15	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0080	D;D
Vest4		0.17
MutPred		0.28		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.61
ClinPred		0.86	D
GERP RS		5.6
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs548940033; hg19: chr2-39164628;