19-46919541-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_004491.5(ARHGAP35):ā€‹c.866A>Gā€‹(p.Asn289Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00033 ( 0 hom., cov: 32)
Exomes š‘“: 0.000063 ( 0 hom. )

Consequence

ARHGAP35
NM_004491.5 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.45
Variant links:
Genes affected
ARHGAP35 (HGNC:4591): (Rho GTPase activating protein 35) The human glucocorticoid receptor DNA binding factor, which associates with the promoter region of the glucocorticoid receptor gene (hGR gene), is a repressor of glucocorticoid receptor transcription. The amino acid sequence deduced from the cDNA sequences show the presence of three sequence motifs characteristic of a zinc finger and one motif suggestive of a leucine zipper in which 1 cysteine is found instead of all leucines. The GRLF1 enhances the homologous down-regulation of wild-type hGR gene expression. Biochemical analysis suggests that GRLF1 interaction is sequence specific and that transcriptional efficacy of GRLF1 is regulated through its interaction with specific sequence motif. The level of expression is regulated by glucocorticoids. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.04373339).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000328 (50/152324) while in subpopulation AFR AF= 0.00103 (43/41580). AF 95% confidence interval is 0.000789. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARHGAP35NM_004491.5 linkuse as main transcriptc.866A>G p.Asn289Ser missense_variant 2/7 ENST00000672722.1 NP_004482.4 Q9NRY4
ARHGAP35XM_024451473.2 linkuse as main transcriptc.866A>G p.Asn289Ser missense_variant 2/7 XP_024307241.1
ARHGAP35XR_002958305.2 linkuse as main transcriptn.1267A>G non_coding_transcript_exon_variant 2/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARHGAP35ENST00000672722.1 linkuse as main transcriptc.866A>G p.Asn289Ser missense_variant 2/7 NM_004491.5 ENSP00000500409.1 Q9NRY4

Frequencies

GnomAD3 genomes
AF:
0.000329
AC:
50
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00104
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000112
AC:
28
AN:
248948
Hom.:
0
AF XY:
0.000111
AC XY:
15
AN XY:
135080
show subpopulations
Gnomad AFR exome
AF:
0.00142
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:
0.0000465
Gnomad NFE exome
AF:
0.0000443
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000629
AC:
92
AN:
1461680
Hom.:
0
Cov.:
32
AF XY:
0.0000646
AC XY:
47
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.000956
Gnomad4 AMR exome
AF:
0.00
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:
0.0000504
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000328
AC:
50
AN:
152324
Hom.:
0
Cov.:
32
AF XY:
0.000322
AC XY:
24
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.00103
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:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000116
Hom.:
0
Bravo
AF:
0.000382
ESP6500AA
AF:
0.00125
AC:
5
ESP6500EA
AF:
0.000239
AC:
2
ExAC
AF:
0.000107
AC:
13
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 submitterclinical testingAmbry GeneticsJul 26, 2021The c.866A>G (p.N289S) alteration is located in exon 1 (coding exon 1) of the ARHGAP35 gene. This alteration results from a A to G substitution at nucleotide position 866, causing the asparagine (N) at amino acid position 289 to be replaced by a serine (S). 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
0.095
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
T;T
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;.
M_CAP
Benign
0.0080
T
MetaRNN
Benign
0.044
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L;L
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-1.6
.;N
REVEL
Benign
0.10
Sift
Benign
0.054
.;T
Sift4G
Benign
0.21
T;T
Vest4
0.49
MVP
0.31
MPC
1.1
ClinPred
0.10
T
GERP RS
6.0
Varity_R
0.16
gMVP
0.35

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.

Other links and lift over

dbSNP: rs201054991; hg19: chr19-47422798; API