11-73308913-C-T

Variant names:

• chr11-73308913-C-T
• rs757602578
• NM_014786.4:c.275C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014786.4(ARHGEF17):​c.275C>T​(p.Pro92Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000044 in 1,363,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: ARHGEF17 NM_014786.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.333
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040673792).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014786.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF17	NM_014786.4	MANE Select	c.275C>T	p.Pro92Leu	missense	Exon 1 of 21	NP_055601.2
	ARHGEF17-AS1	NR_147696.1		n.449G>A		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF17	ENST00000263674.4	TSL:1 MANE Select	c.275C>T	p.Pro92Leu	missense	Exon 1 of 21	ENSP00000263674.3	Q96PE2
	ARHGEF17	ENST00000914587.1		c.275C>T	p.Pro92Leu	missense	Exon 1 of 20	ENSP00000584647.1
	ARHGEF17-AS1	ENST00000546324.1	TSL:2	n.449G>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000663 AC: 1 AN: 15088 AF XY: 0.000102

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000165 AC: 2 AN: 1211320 Hom.: 0 Cov.: 30 AF XY: 0.00000170 AC XY: 1 AN XY: 587046

African (AFR) AF: 0.0000422 AC: 1 AN: 23670

American (AMR) AF: 0.00 AC: 0 AN: 10522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18080

East Asian (EAS) AF: 0.00 AC: 0 AN: 27038

South Asian (SAS) AF: 0.0000190 AC: 1 AN: 52764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 996506

Other (OTH) AF: 0.00 AC: 0 AN: 49794

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

African (AFR) AF: 0.0000724 AC: 3 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000617 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.33
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.055
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.0010	B
Vest4		0.20
MutPred		0.19		Loss of loop (P = 0.0128)
MVP		0.24
MPC		0.39
ClinPred		0.15	T
GERP RS		0.26
Varity_R		0.083
gMVP		0.18
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs757602578; hg19: chr11-73019958;