19-46919050-T-C

Position:

• chr19-46919050-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004491.5(ARHGAP35):​c.375T>C​(p.Leu125Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00829 in 1,613,984 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (83 hom.)
• Consequence: ARHGAP35 NM_004491.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.307

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 19-46919050-T-C is Benign according to our data. Variant chr19-46919050-T-C is described in ClinVar as [Benign]. Clinvar id is 774356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.307 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00693 (1056/152282) while in subpopulation SAS AF= 0.0203 (98/4830). AF 95% confidence interval is 0.017. There are 5 homozygotes in gnomad4. There are 516 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1056 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP35	NM_004491.5	c.375T>C	p.Leu125Leu	synonymous_variant	2/7	ENST00000672722.1	NP_004482.4
ARHGAP35	XM_024451473.2	c.375T>C	p.Leu125Leu	synonymous_variant	2/7		XP_024307241.1
ARHGAP35	XR_002958305.2	n.776T>C		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP35	ENST00000672722.1	c.375T>C	p.Leu125Leu	synonymous_variant	2/7		NM_004491.5	ENSP00000500409.1

Frequencies

GnomAD3 genomes AF: 0.00687 AC: 1046 AN: 152164 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00459

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0194

Gnomad FIN AF: 0.00716

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00888

Gnomad OTH AF: 0.00577

GnomAD3 exomes AF: 0.00810 AC: 2018 AN: 249158 Hom.: 15 AF XY: 0.00888 AC XY: 1200 AN XY: 135160

Gnomad AFR exome AF: 0.00555

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0200

Gnomad FIN exome AF: 0.00854

Gnomad NFE exome AF: 0.00829

Gnomad OTH exome AF: 0.00909

GnomAD4 exome AF: 0.00843 AC: 12320 AN: 1461702 Hom.: 83 Cov.: 32 AF XY: 0.00884 AC XY: 6428 AN XY: 727132

Gnomad4 AFR exome AF: 0.00526

Gnomad4 AMR exome AF: 0.00376

Gnomad4 ASJ exome AF: 0.00187

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0213

Gnomad4 FIN exome AF: 0.00826

Gnomad4 NFE exome AF: 0.00817

Gnomad4 OTH exome AF: 0.00831

GnomAD4 genome AF: 0.00693 AC: 1056 AN: 152282 Hom.: 5 Cov.: 32 AF XY: 0.00693 AC XY: 516 AN XY: 74470

Gnomad4 AFR AF: 0.00469

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0203

Gnomad4 FIN AF: 0.00716

Gnomad4 NFE AF: 0.00889

Gnomad4 OTH AF: 0.00571

Alfa AF: 0.00774 Hom.: 1

Bravo AF: 0.00606

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.00981

EpiControl AF: 0.00842

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 28, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.41
DANN	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs112108478; hg19: chr19-47422307;