X-63638103-A-C

Position:

• chrX-63638103-A-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001353921.2(ARHGEF9):​c.1497T>G​(p.Phe499Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F499F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARHGEF9 NM_001353921.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.22

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25487772).
• BP6: Variant X-63638103-A-C is Benign according to our data. Variant chrX-63638103-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1301616.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF9	NM_001353921.2	c.1497T>G	p.Phe499Leu	missense_variant	10/10	ENST00000671741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF9	ENST00000671741.2	c.1497T>G	p.Phe499Leu	missense_variant	10/10		NM_001353921.2	A1

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111344 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33526

Gnomad AFR AF: 0.00

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: 0.00420

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 8 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 1301616). This missense change has been observed in individual(s) with epileptic encephalopathy with cerebellar atrophy (PMID: 31054490). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 492 of the ARHGEF9 protein (p.Phe492Leu). -
Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Feb 03, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T;.;T;T;T;T;T;T;.;T;.;T;T;.;T;.;T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T;T;T;.;T;.;.;.;T;.;T;.;.;T;.;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-2.3	N;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.
REVEL	Uncertain	0.36
Sift	Benign	0.36	T;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Sift4G	Benign	0.42	T;T;.;.;.;.;.;.;T;T;.;.;.;.;T;T;.
Polyphen		0.0060	B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.33
MutPred		0.38		Loss of phosphorylation at T495 (P = 0.1504);Loss of phosphorylation at T495 (P = 0.1504);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.92
MPC		1.2
ClinPred		0.45	T
GERP RS		1.6
Varity_R		0.31
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-62857983;