chr13-111205296-A-C

Position:

• chr13-111205296-A-C

Variant summary

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

The NM_001354046.2(ARHGEF7):​c.260A>C​(p.Asp87Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ARHGEF7 NM_001354046.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

ARHGEF7 (HGNC:15607): (Rho guanine nucleotide exchange factor 7) This gene encodes a protein that belongs to a family of cytoplasmic proteins that activate the Ras-like family of Rho proteins by exchanging bound GDP for GTP. It forms a complex with the small GTP binding protein Rac1 and recruits Rac1 to membrane ruffles and to focal adhesions. Multiple alternatively spliced transcript variants encoding different isoforms have been observed for this gene. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF7	NM_001354046.2	c.260A>C	p.Asp87Ala	missense_variant	3/22	ENST00000646102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF7	ENST00000646102.2	c.260A>C	p.Asp87Ala	missense_variant	3/22		NM_001354046.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448756 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720614

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000249

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: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

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

May 15, 2024

The c.323A>C (p.D108A) alteration is located in exon 4 (coding exon 4) of the ARHGEF7 gene. This alteration results from a A to C substitution at nucleotide position 323, causing the aspartic acid (D) at amino acid position 108 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	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;.;T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	T;D;D;T;D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.4	.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N;N;N;.;D
REVEL	Benign	0.27
Sift	Uncertain	0.019	D;D;D;.;D
Sift4G	Uncertain	0.038	D;D;D;.;D
Polyphen		0.76	P;P;P;.;.
Vest4		0.46
MutPred		0.50		.;.;Gain of catalytic residue at D108 (P = 0.1386);.;.;
MVP		0.84
MPC		1.7
ClinPred		0.92	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.36

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: rs1271171759; hg19: chr13-111857643;