11-73308672-C-T

Variant names:

• chr11-73308672-C-T
• rs754040307
• NM_014786.4:c.34C>T

Variant summary

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

The NM_014786.4(ARHGEF17):​c.34C>T​(p.Arg12Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,365,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ARHGEF17 NM_014786.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.969

Genes affected

ARHGEF17 (HGNC:21726): (Rho guanine nucleotide exchange factor 17) Enables guanyl-nucleotide exchange factor activity. Acts upstream of or within actin cytoskeleton organization. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ARHGEF17-AS1 (HGNC:55485): (ARHGEF17 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF17	NM_014786.4	c.34C>T	p.Arg12Cys	missense_variant	Exon 1 of 21	ENST00000263674.4	NP_055601.2
ARHGEF17-AS1	NR_147696.1	n.690G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF17	ENST00000263674.4	c.34C>T	p.Arg12Cys	missense_variant	Exon 1 of 21	1	NM_014786.4	ENSP00000263674.3
ARHGEF17-AS1	ENST00000546324.1	n.690G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000268 AC: 3 AN: 111860 Hom.: 0 AF XY: 0.0000157 AC XY: 1 AN XY: 63558

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: 0.000102

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000342

GnomAD4 exome AF: 0.0000103 AC: 14 AN: 1365096 Hom.: 0 Cov.: 30 AF XY: 0.0000163 AC XY: 11 AN XY: 674814

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000330

Gnomad4 SAS exome AF: 0.0000392

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000375

Gnomad4 OTH exome AF: 0.000106

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.0000180 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34C>T (p.R12C) alteration is located in exon 1 (coding exon 1) of the ARHGEF17 gene. This alteration results from a C to T substitution at nucleotide position 34, causing the arginine (R) at amino acid position 12 to be replaced by a cysteine (C). 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
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	0.0066	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.69	N
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.61		Loss of MoRF binding (P = 0.0065);
MVP		0.71
MPC		0.78
ClinPred		0.22	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.25
gMVP		0.58

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: rs754040307; hg19: chr11-73019717;