chr1-156937323-T-C

Variant names:

• chr1-156937323-T-C
• rs868188
• NM_198236.3:c.4366A>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.4366A>G​(p.Ser1456Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,613,488 control chromosomes in the GnomAD database, including 111,136 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1456C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.34 (9079 hom., cov: 31)
  • Exomes 𝑓: 0.37 (102057 hom.)
• Consequence: ARHGEF11 NM_198236.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 28 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=3.9103627E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.479 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.4366A>G	p.Ser1456Gly	missense	Exon 39 of 41	NP_937879.1	O15085-2
	ARHGEF11	NM_001377418.1		c.4357A>G	p.Ser1453Gly	missense	Exon 39 of 41	NP_001364347.1
	ARHGEF11	NM_001377419.1		c.4336A>G	p.Ser1446Gly	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.4366A>G	p.Ser1456Gly	missense	Exon 39 of 41	ENSP00000357177.3	O15085-2
	ARHGEF11	ENST00000361409.2	TSL:1	c.4246A>G	p.Ser1416Gly	missense	Exon 38 of 40	ENSP00000354644.2	O15085-1
	ARHGEF11	ENST00000715594.1		c.4414A>G	p.Ser1472Gly	missense	Exon 41 of 43	ENSP00000520488.1	A0AAQ5BIK5

Frequencies

GnomAD3 genomes AF: 0.336 AC: 50969 AN: 151850 Hom.: 9074 Cov.: 31

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.361

GnomAD2 exomes AF: 0.402 AC: 100829 AN: 250858 AF XY: 0.401

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.558

Gnomad ASJ exome AF: 0.391

Gnomad EAS exome AF: 0.496

Gnomad FIN exome AF: 0.367

Gnomad NFE exome AF: 0.352

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.369 AC: 539469 AN: 1461518 Hom.: 102057 Cov.: 53 AF XY: 0.372 AC XY: 270569 AN XY: 727062

African (AFR) AF: 0.219 AC: 7345 AN: 33464

American (AMR) AF: 0.545 AC: 24340 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 10236 AN: 26100

East Asian (EAS) AF: 0.469 AC: 18632 AN: 39696

South Asian (SAS) AF: 0.477 AC: 41115 AN: 86226

European-Finnish (FIN) AF: 0.365 AC: 19464 AN: 53384

Middle Eastern (MID) AF: 0.311 AC: 1791 AN: 5764

European-Non Finnish (NFE) AF: 0.354 AC: 394126 AN: 1111818

Other (OTH) AF: 0.371 AC: 22420 AN: 60380

GnomAD4 genome AF: 0.335 AC: 50979 AN: 151970 Hom.: 9079 Cov.: 31 AF XY: 0.339 AC XY: 25198 AN XY: 74266

African (AFR) AF: 0.224 AC: 9269 AN: 41440

American (AMR) AF: 0.443 AC: 6772 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1384 AN: 3472

East Asian (EAS) AF: 0.495 AC: 2551 AN: 5150

South Asian (SAS) AF: 0.484 AC: 2324 AN: 4800

European-Finnish (FIN) AF: 0.359 AC: 3801 AN: 10576

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.349 AC: 23738 AN: 67944

Other (OTH) AF: 0.357 AC: 753 AN: 2108

Alfa AF: 0.354 Hom.: 31363

Bravo AF: 0.338

TwinsUK AF: 0.352 AC: 1306

ALSPAC AF: 0.361 AC: 1391

ESP6500AA AF: 0.224 AC: 987

ESP6500EA AF: 0.357 AC: 3067

ExAC AF: 0.394 AC: 47792

Asia WGS AF: 0.456 AC: 1587 AN: 3476

EpiCase AF: 0.349

EpiControl AF: 0.357

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.00039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.13
Sift	Benign	0.11	T
Sift4G	Uncertain	0.053	T
Polyphen		0.0030	B
Vest4		0.038
MPC		0.032
ClinPred		0.0037	T
GERP RS		0.50
Varity_R		0.10
gMVP		0.20
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs868188; hg19: chr1-156907115; COSMIC: COSV59354781; COSMIC: COSV59354781;