Variant chr7-144187138-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000378115.3(ARHGEF35):c.1246T>G(p.Ser416Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000091 ( 1 hom., cov: 20)

Exomes 𝑓: 0.00012 ( 23 hom. )

Failed GnomAD Quality Control

Consequence

ARHGEF35
ENST00000378115.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.243

Variant links:

Genes affected

ARHGEF35 (HGNC:33846): (Rho guanine nucleotide exchange factor 35)

ARHGEF35 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011888981).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF35	NM_001003702.3 linkuse as main transcript	c.1246T>G	p.Ser416Ala	missense_variant	2/2	ENST00000378115.3	NP_001003702.2
ARHGEF35	NM_001368318.1 linkuse as main transcript	c.1246T>G	p.Ser416Ala	missense_variant	2/2		NP_001355247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF35	ENST00000378115.3 linkuse as main transcript	c.1246T>G	p.Ser416Ala	missense_variant	2/2	1	NM_001003702.3	ENSP00000367355	P1
ARHGEF35	ENST00000688754.1 linkuse as main transcript	c.1246T>G	p.Ser416Ala	missense_variant	2/2			ENSP00000510684	P1

Frequencies

GnomAD3 genomes

AF:

0.0000908

AC:

AN:

132172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000749

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00137

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000842

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000161

AC:

AN:

198624

Hom.:

AF XY:

0.000260

AC XY:

AN XY:

107766

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000323

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000494

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000121

AC:

168

AN:

1388422

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

109

AN XY:

691078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000232

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000729

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000800

Gnomad4 OTH exome

AF:

0.000346

GnomAD4 genome

AF:

0.0000907

AC:

AN:

132282

Hom.:

Cov.:

AF XY:

0.0000933

AC XY:

AN XY:

64326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000748

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00137

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000842

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000124

Hom.:

ExAC

AF:

0.000199

AC:

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

Jan 03, 2024

The c.1246T>G (p.S416A) alteration is located in exon 2 (coding exon 1) of the ARHGEF35 gene. This alteration results from a T to G substitution at nucleotide position 1246, causing the serine (S) at amino acid position 416 to be replaced by an alanine (A). 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

0.12

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.4

DANN

Benign

0.90

DEOGEN2

Benign

0.028

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.27

M_CAP

Benign

0.0028

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

N;N

PROVEAN

Benign

-0.93

REVEL

Benign

0.055

Sift

Benign

1.0

Sift4G

Benign

0.14

Polyphen

0.67

Vest4

0.11

MutPred

0.18

Loss of glycosylation at S416 (P = 0.0429);

MVP

0.040

MPC

1.8

ClinPred

0.030

GERP RS

-3.3

Varity_R

0.045

gMVP

0.0097

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