X-63635344-T-C

Position:

chrX-63635344-T-C

Variant summary

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

The ENST00000374878.5(ARHGEF9):c.1439A>G(p.Asn480Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 520,387 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000037 ( 0 hom. 4 hem. )

Consequence

ARHGEF9
ENST00000374878.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.737

Variant links:

Genes affected

ARHGEF9 (HGNC:14561): (Cdc42 guanine nucleotide exchange factor 9) The protein encoded by this gene is a Rho-like GTPase that switches between the active (GTP-bound) state and inactive (GDP-bound) state to regulate CDC42 and other genes. This brain-specific protein also acts as an adaptor protein for the recruitment of gephyrin and together these proteins facilitate receceptor recruitement in GABAnergic and glycinergic synapses. Defects in this gene are the cause of startle disease with epilepsy (STHEE), also known as hyperekplexia with epilepsy, as well as several other types of cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

ARHGEF9 links:

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=0.00903374).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000143 (16/111833) while in subpopulation AMR AF= 0.00142 (15/10556). AF 95% confidence interval is 0.000876. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF9	NM_001353921.2 linkuse as main transcript	c.*2684A>G		3_prime_UTR_variant	10/10	ENST00000671741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF9	ENST00000671741.2 linkuse as main transcript	c.*2684A>G		3_prime_UTR_variant	10/10		NM_001353921.2	A1

Frequencies

GnomAD3 genomes

AF:

0.000143

AC:

AN:

111776

Hom.:

Cov.:

AF XY:

0.0000883

AC XY:

AN XY:

33966

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00142

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000194

AC:

AN:

102990

Hom.:

AF XY:

0.00

AC XY:

AN XY:

33544

show subpopulations

Gnomad AFR exome

AF:

0.000199

Gnomad AMR exome

AF:

0.0000571

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000367

AC:

AN:

408554

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

148932

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000424

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:

0.00

Gnomad4 OTH exome

AF:

0.000173

GnomAD4 genome

AF:

0.000143

AC:

AN:

111833

Hom.:

Cov.:

AF XY:

0.0000881

AC XY:

AN XY:

34033

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00142

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000162

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Global developmental delay

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Mar 17, 2020

The hemizygous c*2684A>G variant is a rare variant in the 3' UTR of the ARHGEF9 gene (exon 9/9, 3' UTR position 2866/3243). The Adenine nucleotide at this position is well conserved. This variant is found with low frequency in gnomAD (2 heterozygotes, 0 homozygotes, 0 hemizygotes; allele frequency: 1.94e-5) suggesting it is not a common benign variant in the populations represented in this database. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature. This variant was detected hemizygous in a male, and inherited from a presumably unaffected mother in an indiviudal submitted for clincial WGS testing. The c.*2684A>G variant in the ARHGEF9 gene is reported here as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.52

DANN

Benign

0.34

DEOGEN2

Benign

0.0076

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.27

M_CAP

Benign

0.0047

MetaRNN

Benign

0.0090

MetaSVM

Benign

-0.85

MutationTaster

Benign

1.0

N;N;N;N

REVEL

Benign

0.055

Sift4G

Benign

0.71

Vest4

0.092

MVP

0.26

ClinPred

0.0094

GERP RS

-2.5

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