Variant 7-144187269-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001003702.3(ARHGEF35):c.1115G>C(p.Ser372Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,207,584 control chromosomes in the GnomAD database, including 27 homozygotes. 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 0.00014 ( 2 hom., cov: 19)

Exomes 𝑓: 0.00011 ( 27 hom. )

Failed GnomAD Quality Control

Consequence

ARHGEF35
NM_001003702.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0900

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.034009367).

BS2

High Homozygotes in GnomAdExome4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF35	NM_001003702.3 linkuse as main transcript	c.1115G>C	p.Ser372Thr	missense_variant	2/2	ENST00000378115.3	NP_001003702.2	A5YM69
ARHGEF35	NM_001368318.1 linkuse as main transcript	c.1115G>C	p.Ser372Thr	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.1115G>C	p.Ser372Thr	missense_variant	2/2	1	NM_001003702.3	ENSP00000367355.3		A5YM69
ARHGEF35	ENST00000688754.1 linkuse as main transcript	c.1115G>C	p.Ser372Thr	missense_variant	2/2			ENSP00000510684.1		A5YM69

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

124432

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000878

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000417

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:

0.000161

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000581

AC:

AN:

189442

Hom.:

AF XY:

0.0000783

AC XY:

AN XY:

102220

show subpopulations

Gnomad AFR exome

AF:

0.0000720

Gnomad AMR exome

AF:

0.0000443

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:

0.000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000106

AC:

128

AN:

1207584

Hom.:

Cov.:

AF XY:

0.0000912

AC XY:

AN XY:

603152

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000627

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:

0.000135

Gnomad4 OTH exome

AF:

0.0000584

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000137

AC:

AN:

124432

Hom.:

Cov.:

AF XY:

0.0000999

AC XY:

AN XY:

60082

show subpopulations

Gnomad4 AFR

AF:

0.0000878

Gnomad4 AMR

AF:

0.000417

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000161

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000404

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 20, 2023

The c.1115G>C (p.S372T) alteration is located in exon 2 (coding exon 1) of the ARHGEF35 gene. This alteration results from a G to C substitution at nucleotide position 1115, causing the serine (S) at amino acid position 372 to be replaced by a threonine (T). 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

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.14

DANN

Benign

0.63

DEOGEN2

Benign

0.014

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.22

M_CAP

Benign

0.0022

MetaRNN

Benign

0.034

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PROVEAN

Benign

-1.0

REVEL

Benign

0.020

Sift

Benign

0.54

Sift4G

Benign

0.28

Polyphen

0.35

Vest4

0.034

MutPred

0.15

Loss of glycosylation at S372 (P = 0.0087);

MVP

0.030

MPC

1.1

ClinPred

0.014

GERP RS

-0.81

Varity_R

0.058

gMVP

0.0059

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