chr10-97244060-T-C

Position:

• chr10-97244060-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032900.6(ARHGAP19):​c.1093A>G​(p.Thr365Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ARHGAP19 NM_032900.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.31

Genes affected

ARHGAP19 (HGNC:23724): (Rho GTPase activating protein 19) Members of the ARHGAP family, such as ARHGAP19, encode negative regulators of Rho GTPases (see RHOA; MIM 165390), which are involved in cell migration, proliferation, and differentiation, actin remodeling, and G1 cell cycle progression (Lv et al., 2007 [PubMed 17454002]).[supplied by OMIM, Mar 2008]

ARHGAP19-SLIT1 (HGNC:48348): (ARHGAP19-SLIT1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring Rho GTPase activating protein 19 (ARHGAP19) and slit homolog 1 (SLIT1) genes on chromosome 10. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ARHGAP19 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12960747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP19	NM_032900.6	c.1093A>G	p.Thr365Ala	missense_variant	8/12	ENST00000358531.9	NP_116289.4
ARHGAP19	NM_001256423.2	c.1066A>G	p.Thr356Ala	missense_variant	8/12		NP_001243352.1
ARHGAP19	NM_001204300.2	c.1006A>G	p.Thr336Ala	missense_variant	7/11		NP_001191229.1
ARHGAP19-SLIT1	NR_037909.1	n.1139A>G		non_coding_transcript_exon_variant	8/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP19	ENST00000358531.9	c.1093A>G	p.Thr365Ala	missense_variant	8/12	1	NM_032900.6	ENSP00000351333.4
ARHGAP19-SLIT1	ENST00000479633.2	n.1093A>G		non_coding_transcript_exon_variant	8/15	2		ENSP00000473567.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.0000166

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

Aug 16, 2022

The c.1093A>G (p.T365A) alteration is located in exon 8 (coding exon 8) of the ARHGAP19 gene. This alteration results from a A to G substitution at nucleotide position 1093, causing the threonine (T) at amino acid position 365 to be replaced by an alanine (A). 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	Benign	0.078
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.;.
Eigen	Benign	-0.051
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.9	N;D;N
REVEL	Benign	0.055
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.0030	B;B;B
Vest4		0.38
MutPred		0.25		Loss of phosphorylation at T365 (P = 0.0377);.;.;
MVP		0.21
MPC		0.21
ClinPred		0.80	D
GERP RS		4.7
Varity_R		0.072
gMVP		0.19

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: rs1842527679; hg19: chr10-99003817;