19-46919091-T-C

Position:

• chr19-46919091-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004491.5(ARHGAP35):​c.416T>C​(p.Leu139Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGAP35 NM_004491.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP35	NM_004491.5	c.416T>C	p.Leu139Pro	missense_variant	2/7	ENST00000672722.1	NP_004482.4
ARHGAP35	XM_024451473.2	c.416T>C	p.Leu139Pro	missense_variant	2/7		XP_024307241.1
ARHGAP35	XR_002958305.2	n.817T>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.416T>C	p.Leu139Pro	missense_variant	2/7		NM_004491.5	ENSP00000500409.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2022

The c.416T>C (p.L139P) alteration is located in exon 1 (coding exon 1) of the ARHGAP35 gene. This alteration results from a T to C substitution at nucleotide position 416, causing the leucine (L) at amino acid position 139 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;.
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.7	.;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.89
MutPred		0.74		Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);
MVP		0.90
MPC		2.1
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.97
gMVP		0.95

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: chr19-47422348;