1-16206964-T-G

Position:

• chr1-16206964-T-G

Variant summary

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

The NM_153213.5(ARHGEF19):​c.1121A>C​(p.Asp374Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000148 in 1,349,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ARHGEF19 NM_153213.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.56

Genes affected

ARHGEF19 (HGNC:26604): (Rho guanine nucleotide exchange factor 19) Guanine nucleotide exchange factors (GEFs) such as ARHGEF19 accelerate the GTPase activity of Rho GTPases (see RHOA, MIM 165390).[supplied by OMIM, Dec 2008]

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=0.22114462).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF19	NM_153213.5	c.1121A>C	p.Asp374Ala	missense_variant	6/16	ENST00000270747.8	NP_694945.2
ARHGEF19	XM_011540706.4	c.1121A>C	p.Asp374Ala	missense_variant	7/17		XP_011539008.1
ARHGEF19	XR_946544.2	n.1301A>C		non_coding_transcript_exon_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF19	ENST00000270747.8	c.1121A>C	p.Asp374Ala	missense_variant	6/16	1	NM_153213.5	ENSP00000270747	P1
ARHGEF19	ENST00000478117.5	n.48A>C		non_coding_transcript_exon_variant	1/11	1
ARHGEF19	ENST00000471928.1	n.19A>C		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000148 AC: 2 AN: 1349610 Hom.: 0 Cov.: 33 AF XY: 0.00000150 AC XY: 1 AN XY: 665664

Gnomad4 AFR exome AF: 0.0000368

Gnomad4 AMR exome AF: 0.00

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: 9.40e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Apr 11, 2023

The c.1121A>C (p.D374A) alteration is located in exon 6 (coding exon 5) of the ARHGEF19 gene. This alteration results from a A to C substitution at nucleotide position 1121, causing the aspartic acid (D) at amino acid position 374 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	0.28
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.040
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.098
Sift	Benign	0.057	T
Sift4G	Uncertain	0.020	D
Polyphen		0.19	B
Vest4		0.23
MutPred		0.63		Loss of ubiquitination at K376 (P = 0.0901);
MVP		0.44
MPC		0.33
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.19
gMVP		0.44

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: rs1004581538; hg19: chr1-16533459;