rs11860295

Positions:

• chr16-67282331-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001129729.3(PLEKHG4):​c.1235C>T​(p.Thr412Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,612,318 control chromosomes in the GnomAD database, including 18,869 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.22 (7367 hom., cov: 32)
  • Exomes 𝑓: 0.092 (11502 hom.)
• Consequence: PLEKHG4 NM_001129729.3 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.195

Genes affected

PLEKHG4 (HGNC:24501): (pleckstrin homology and RhoGEF domain containing G4) The protein encoded by this gene can function as a guanine nucleotide exchange factor (GEF) and may play a role in intracellular signaling and cytoskeleton dynamics at the Golgi apparatus. Polymorphisms in the region of this gene have been found to be associated with spinocerebellar ataxia in some study populations. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.3336244E-5).
• BP6: Variant 16-67282331-C-T is Benign according to our data. Variant chr16-67282331-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129964.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG4	NM_001129729.3	c.1235C>T	p.Thr412Ile	missense_variant	9/22	ENST00000379344.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG4	ENST00000379344.8	c.1235C>T	p.Thr412Ile	missense_variant	9/22	1	NM_001129729.3	P2

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33238 AN: 151984 Hom.: 7331 Cov.: 32

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.00484

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.0740

Gnomad OTH AF: 0.169

GnomAD3 exomes AF: 0.118 AC: 29259 AN: 247982 Hom.: 3773 AF XY: 0.113 AC XY: 15221 AN XY: 134436

Gnomad AFR exome AF: 0.582

Gnomad AMR exome AF: 0.0660

Gnomad ASJ exome AF: 0.0681

Gnomad EAS exome AF: 0.00404

Gnomad SAS exome AF: 0.152

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.0787

Gnomad OTH exome AF: 0.0957

GnomAD4 exome AF: 0.0922 AC: 134694 AN: 1460216 Hom.: 11502 Cov.: 35 AF XY: 0.0921 AC XY: 66903 AN XY: 726364

Gnomad4 AFR exome AF: 0.594

Gnomad4 AMR exome AF: 0.0696

Gnomad4 ASJ exome AF: 0.0703

Gnomad4 EAS exome AF: 0.00272

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.140

Gnomad4 NFE exome AF: 0.0741

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.219 AC: 33320 AN: 152102 Hom.: 7367 Cov.: 32 AF XY: 0.217 AC XY: 16161 AN XY: 74374

Gnomad4 AFR AF: 0.571

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0605

Gnomad4 EAS AF: 0.00485

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.0740

Gnomad4 OTH AF: 0.167

Alfa AF: 0.106 Hom.: 3243

Bravo AF: 0.228

TwinsUK AF: 0.0787 AC: 292

ALSPAC AF: 0.0784 AC: 302

ESP6500AA AF: 0.558 AC: 2454

ESP6500EA AF: 0.0749 AC: 644

ExAC AF: 0.129 AC: 15692

Asia WGS AF: 0.122 AC: 424 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T;T;T;.
Eigen	Benign	-0.079
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.58	.;.;T;T
MetaRNN	Benign	0.000043	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;M;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.27	T;T;T;T
Sift4G	Benign	0.078	T;T;T;T
Polyphen		0.27	B;B;B;D
Vest4		0.057
MPC		0.29
ClinPred		0.017	T
GERP RS		3.2
Varity_R		0.036
gMVP		0.15

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: rs11860295; hg19: chr16-67316234;