X-63635344-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.737

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 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 GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF9	NM_001353921.2	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	c.*2684A>G		3_prime_UTR_variant	10/10		NM_001353921.2	A1

Frequencies

GnomAD3 genomes AF: 0.000143 AC: 16 AN: 111776 Hom.: 0 Cov.: 22 AF XY: 0.0000883 AC XY: 3 AN XY: 33966

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: 2 AN: 102990 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 33544

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: 15 AN: 408554 Hom.: 0 Cov.: 0 AF XY: 0.0000269 AC XY: 4 AN XY: 148932

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: 16 AN: 111833 Hom.: 0 Cov.: 22 AF XY: 0.0000881 AC XY: 3 AN XY: 34033

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

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	T
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.52
Dann	Benign	0.34
DEOGEN2	Benign	0.0076	T
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	N;N;N;N
REVEL	Benign	0.055
Sift4G	Benign	0.71	T
Vest4		0.092
MVP		0.26
ClinPred		0.0094	T
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

Other links and lift over

dbSNP: rs189661969; hg19: chrX-62855224; COSMIC: COSV53636209; COSMIC: COSV53636209;