Variant 1-3463659-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014448.4(ARHGEF16):c.575C>T(p.Pro192Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000709 in 1,409,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

ARHGEF16
NM_014448.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.568

Variant links:

Genes affected

ARHGEF16 (HGNC:15515): (Rho guanine nucleotide exchange factor 16) Although the specific function of this protein is not known yet, it is thought to be involved in protein-protein and protein-lipid interactions. [provided by RefSeq, Jul 2008]

ARHGEF16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.066015095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF16	NM_014448.4 link	c.575C>T	p.Pro192Leu	missense_variant	2/15	ENST00000378378.9	NP_055263.2	Q5VV41-1B3KTS4
ARHGEF16	XM_017001049.2 link	c.626C>T	p.Pro209Leu	missense_variant	2/15		XP_016856538.1
ARHGEF16	XM_017001051.2 link	c.575C>T	p.Pro192Leu	missense_variant	2/15		XP_016856540.1	Q5VV41-1
ARHGEF16	XM_047418009.1 link	c.626C>T	p.Pro209Leu	missense_variant	2/8		XP_047273965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF16	ENST00000378378.9 link	c.575C>T	p.Pro192Leu	missense_variant	2/15	2	NM_014448.4	ENSP00000367629.4		Q5VV41-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000436

AC:

AN:

68840

Hom.:

AF XY:

0.0000290

AC XY:

AN XY:

34434

show subpopulations

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:

0.0000781

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.00000716

AC:

AN:

1257754

Hom.:

Cov.:

AF XY:

0.00000496

AC XY:

AN XY:

604594

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000533

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:

0.00000695

Gnomad4 OTH exome

AF:

0.0000193

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000123

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2024

The c.575C>T (p.P192L) alteration is located in exon 2 (coding exon 1) of the ARHGEF16 gene. This alteration results from a C to T substitution at nucleotide position 575, causing the proline (P) at amino acid position 192 to be replaced by a leucine (L). 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

Benign

0.070

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.042

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.69

M_CAP

Benign

0.046

MetaRNN

Benign

0.066

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.9

REVEL

Benign

0.060

Sift

Benign

0.44

Sift4G

Benign

0.11

Polyphen

0.048

Vest4

0.062

MutPred

0.14

Loss of glycosylation at P192 (P = 0.0192);

MVP

0.37

MPC

0.33

ClinPred

0.046

GERP RS

1.7

Varity_R

0.049

gMVP

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over