1-156937289-T-C

Variant names:

• chr1-156937289-T-C
• rs945508
• NM_198236.3:c.4400A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198236.3(ARHGEF11):​c.4400A>G​(p.His1467Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 1,613,742 control chromosomes in the GnomAD database, including 280,324 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.66 (34133 hom., cov: 31)
  • Exomes 𝑓: 0.57 (246191 hom.)
• Consequence: ARHGEF11 NM_198236.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.452
• Publications: 52 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.671436E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198236.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF11	NM_198236.3	MANE Select	c.4400A>G	p.His1467Arg	missense	Exon 39 of 41	NP_937879.1	O15085-2
	ARHGEF11	NM_001377418.1		c.4391A>G	p.His1464Arg	missense	Exon 39 of 41	NP_001364347.1
	ARHGEF11	NM_001377419.1		c.4370A>G	p.His1457Arg	missense	Exon 38 of 40	NP_001364348.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF11	ENST00000368194.8	TSL:1 MANE Select	c.4400A>G	p.His1467Arg	missense	Exon 39 of 41	ENSP00000357177.3	O15085-2
	ARHGEF11	ENST00000361409.2	TSL:1	c.4280A>G	p.His1427Arg	missense	Exon 38 of 40	ENSP00000354644.2	O15085-1
	ARHGEF11	ENST00000715594.1		c.4448A>G	p.His1483Arg	missense	Exon 41 of 43	ENSP00000520488.1	A0AAQ5BIK5

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99668 AN: 151920 Hom.: 34062 Cov.: 31

Gnomad AFR AF: 0.838

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.685

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.861

Gnomad SAS AF: 0.712

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.653

GnomAD2 exomes AF: 0.641 AC: 160920 AN: 251118 AF XY: 0.633

Gnomad AFR exome AF: 0.850

Gnomad AMR exome AF: 0.740

Gnomad ASJ exome AF: 0.633

Gnomad EAS exome AF: 0.869

Gnomad FIN exome AF: 0.567

Gnomad NFE exome AF: 0.543

Gnomad OTH exome AF: 0.608

GnomAD4 exome AF: 0.574 AC: 838830 AN: 1461704 Hom.: 246191 Cov.: 60 AF XY: 0.577 AC XY: 419700 AN XY: 727160

African (AFR) AF: 0.850 AC: 28467 AN: 33480

American (AMR) AF: 0.737 AC: 32948 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.631 AC: 16490 AN: 26124

East Asian (EAS) AF: 0.866 AC: 34373 AN: 39700

South Asian (SAS) AF: 0.697 AC: 60139 AN: 86244

European-Finnish (FIN) AF: 0.560 AC: 29894 AN: 53398

Middle Eastern (MID) AF: 0.555 AC: 3198 AN: 5762

European-Non Finnish (NFE) AF: 0.537 AC: 596871 AN: 1111900

Other (OTH) AF: 0.604 AC: 36450 AN: 60382

GnomAD4 genome AF: 0.656 AC: 99795 AN: 152038 Hom.: 34133 Cov.: 31 AF XY: 0.659 AC XY: 48973 AN XY: 74322

African (AFR) AF: 0.838 AC: 34754 AN: 41468

American (AMR) AF: 0.685 AC: 10481 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 2214 AN: 3472

East Asian (EAS) AF: 0.862 AC: 4436 AN: 5146

South Asian (SAS) AF: 0.711 AC: 3429 AN: 4822

European-Finnish (FIN) AF: 0.556 AC: 5877 AN: 10578

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.539 AC: 36621 AN: 67950

Other (OTH) AF: 0.656 AC: 1382 AN: 2106

Alfa AF: 0.590 Hom.: 92142

Bravo AF: 0.674

TwinsUK AF: 0.529 AC: 1963

ALSPAC AF: 0.541 AC: 2086

ESP6500AA AF: 0.840 AC: 3701

ESP6500EA AF: 0.553 AC: 4757

ExAC AF: 0.639 AC: 77584

Asia WGS AF: 0.803 AC: 2792 AN: 3478

EpiCase AF: 0.549

EpiControl AF: 0.555

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.2
DANN	Benign	0.74
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.036	T
MetaRNN	Benign	5.7e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-0.45
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.048
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.038
ClinPred		0.0092	T
GERP RS		-1.6
Varity_R		0.022
gMVP		0.16
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs945508; hg19: chr1-156907081; COSMIC: COSV59355878; COSMIC: COSV59355878;