rs7248026

Variant names:

• chr19-46980746-T-G
• rs7248026
• NM_004491.5:c.3827-7243T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004491.5(ARHGAP35):​c.3827-7243T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 152,070 control chromosomes in the GnomAD database, including 4,755 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (4755 hom., cov: 32)
• Consequence: ARHGAP35 NM_004491.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0290
• Publications: 3 publications found

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]

ARHGAP35 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP35	NM_004491.5	c.3827-7243T>G		intron_variant	Intron 3 of 6	ENST00000672722.1	NP_004482.4
ARHGAP35	XM_024451473.2	c.3827-7243T>G		intron_variant	Intron 3 of 6		XP_024307241.1
ARHGAP35	XR_002958305.2	n.4228-7243T>G		intron_variant	Intron 3 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP35	ENST00000672722.1	c.3827-7243T>G		intron_variant	Intron 3 of 6		NM_004491.5	ENSP00000500409.1
ARHGAP35	ENST00000595822.1	n.90-7243T>G		intron_variant	Intron 1 of 3	2

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37040 AN: 151952 Hom.: 4750 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.0625

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.243

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.244 AC: 37063 AN: 152070 Hom.: 4755 Cov.: 32 AF XY: 0.236 AC XY: 17567 AN XY: 74352

African (AFR) AF: 0.228 AC: 9445 AN: 41470

American (AMR) AF: 0.191 AC: 2924 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 828 AN: 3466

East Asian (EAS) AF: 0.0624 AC: 323 AN: 5174

South Asian (SAS) AF: 0.141 AC: 681 AN: 4822

European-Finnish (FIN) AF: 0.204 AC: 2164 AN: 10584

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19879 AN: 67942

Other (OTH) AF: 0.241 AC: 508 AN: 2112

Alfa AF: 0.271 Hom.: 736

Bravo AF: 0.244

Asia WGS AF: 0.104 AC: 363 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.9
DANN	Benign	0.37
PhyloP100		0.029
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7248026; hg19: chr19-47484003;