Variant 1-16204804-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_153213.5(ARHGEF19):c.1862A>G(p.Tyr621Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000887 in 1,612,420 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00095 ( 1 hom. )

Consequence

ARHGEF19
NM_153213.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.91

Variant links:

Genes affected

ARHGEF19 (HGNC:26604): (Rho guanine nucleotide exchange factor 19) Guanine nucleotide exchange factors (GEFs) such as ARHGEF19 accelerate the GTPase activity of Rho GTPases (see RHOA, MIM 165390).[supplied by OMIM, Dec 2008]

ARHGEF19 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF19	NM_153213.5 linkuse as main transcript	c.1862A>G	p.Tyr621Cys	missense_variant	12/16	ENST00000270747.8	NP_694945.2
ARHGEF19	XM_011540706.4 linkuse as main transcript	c.1862A>G	p.Tyr621Cys	missense_variant	13/17		XP_011539008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF19	ENST00000270747.8 linkuse as main transcript	c.1862A>G	p.Tyr621Cys	missense_variant	12/16	1	NM_153213.5	ENSP00000270747	P1	Q8IW93-1
ARHGEF19	ENST00000478117.5 linkuse as main transcript	n.789A>G		non_coding_transcript_exon_variant	7/11	1
ARHGEF19	ENST00000449495.1 linkuse as main transcript			downstream_gene_variant		2		ENSP00000391145

Frequencies

GnomAD3 genomes

AF:

0.000316

AC:

AN:

151852

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000574

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000365

AC:

AN:

249440

Hom.:

AF XY:

0.000334

AC XY:

AN XY:

134800

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000746

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.000946

AC:

1382

AN:

1460568

Hom.:

Cov.:

AF XY:

0.000870

AC XY:

632

AN XY:

726410

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00118

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.000316

AC:

AN:

151852

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74140

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000574

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000571

Hom.:

Bravo

AF:

0.000408

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000313

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000891

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 03, 2024

The c.1862A>G (p.Y621C) alteration is located in exon 12 (coding exon 11) of the ARHGEF19 gene. This alteration results from a A to G substitution at nucleotide position 1862, causing the tyrosine (Y) at amino acid position 621 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

0.62

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

0.021

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.86

MVP

0.86

MPC

1.0

ClinPred

0.61

GERP RS

4.4

Varity_R

0.52

gMVP

0.67

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