1-156937272-T-C

Position:

• chr1-156937272-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198236.3(ARHGEF11):​c.4417A>G​(p.Thr1473Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1473I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ARHGEF11 NM_198236.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82

Genes affected

ARHGEF11 (HGNC:14580): (Rho guanine nucleotide exchange factor 11) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form a complex with G proteins and stimulate Rho-dependent signals. A similar protein in rat interacts with glutamate transporter EAAT4 and modulates its glutamate transport activity. Expression of the rat protein induces the reorganization of the actin cytoskeleton and its overexpression induces the formation of membrane ruffling and filopodia. Two alternative transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

LRRC71 (HGNC:26556): (leucine rich repeat containing 71)

ARHGEF11 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41296273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF11	NM_198236.3	c.4417A>G	p.Thr1473Ala	missense_variant	39/41	ENST00000368194.8	NP_937879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF11	ENST00000368194.8	c.4417A>G	p.Thr1473Ala	missense_variant	39/41	1	NM_198236.3	ENSP00000357177.3
ARHGEF11	ENST00000361409.2	c.4297A>G	p.Thr1433Ala	missense_variant	38/40	1		ENSP00000354644.2
ARHGEF11	ENST00000487682.5	n.3369A>G		non_coding_transcript_exon_variant	8/10	2
ARHGEF11	ENST00000492592.1	n.651A>G		non_coding_transcript_exon_variant	4/5	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

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 26, 2024

The c.4297A>G (p.T1433A) alteration is located in exon 38 (coding exon 38) of the ARHGEF11 gene. This alteration results from a A to G substitution at nucleotide position 4297, causing the threonine (T) at amino acid position 1433 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	0.23
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.9	.;L
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.10	T;T
Polyphen		1.0	D;D
Vest4		0.48
MutPred		0.22		.;Gain of helix (P = 0.062);
MVP		0.72
MPC		0.11
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.31
gMVP		0.46

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: chr1-156907064;