NM_001145451.5:c.2537C>T

Variant names:

• chr2-38973767-C-T
• rs1409149293
• NM_001145451.5:c.2537C>T

Variant summary

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

The NM_001145451.5(ARHGEF33):​c.2537C>T​(p.Pro846Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGEF33 NM_001145451.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19345239).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF33	NM_001145451.5	c.2537C>T	p.Pro846Leu	missense_variant	Exon 18 of 18	ENST00000409978.7	NP_001138923.2
ARHGEF33	NM_001367623.3	c.*781C>T		3_prime_UTR_variant	Exon 19 of 19		NP_001354552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF33	ENST00000409978.7	c.2537C>T	p.Pro846Leu	missense_variant	Exon 18 of 18	5	NM_001145451.5	ENSP00000387020.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000663 AC: 1 AN: 150862 Hom.: 0 AF XY: 0.0000123 AC XY: 1 AN XY: 81008

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000175

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.70	.;T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.58	T
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.078
Sift	Uncertain	0.017	D;D
Sift4G	Benign	0.12	T;T
Vest4		0.34
MutPred		0.32		Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);
MVP		0.58
ClinPred		0.97	D
GERP RS		4.8
gMVP		0.058

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: rs1409149293; hg19: chr2-39200908;