16-67284339-A-G

Position:

• chr16-67284339-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001129729.3(PLEKHG4):​c.1574A>G​(p.Asp525Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,146 control chromosomes in the GnomAD database, including 26,330 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.26 (9185 hom., cov: 32)
  • Exomes 𝑓: 0.12 (17145 hom.)
• Consequence: PLEKHG4 NM_001129729.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.793

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.837583E-6).
• BP6: Variant 16-67284339-A-G is Benign according to our data. Variant chr16-67284339-A-G is described in ClinVar as [Benign]. Clinvar id is 129965.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG4	NM_001129729.3	c.1574A>G	p.Asp525Gly	missense_variant	12/22	ENST00000379344.8	NP_001123201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHG4	ENST00000379344.8	c.1574A>G	p.Asp525Gly	missense_variant	12/22	1	NM_001129729.3	ENSP00000368649	P2

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38823 AN: 151600 Hom.: 9144 Cov.: 32

Gnomad AFR AF: 0.630

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.0748

Gnomad EAS AF: 0.0309

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.211

GnomAD3 exomes AF: 0.149 AC: 37172 AN: 248826 Hom.: 5007 AF XY: 0.144 AC XY: 19407 AN XY: 134978

Gnomad AFR exome AF: 0.637

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.0869

Gnomad EAS exome AF: 0.0237

Gnomad SAS exome AF: 0.182

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.124 AC: 181773 AN: 1461428 Hom.: 17145 Cov.: 33 AF XY: 0.124 AC XY: 90070 AN XY: 727040

Gnomad4 AFR exome AF: 0.654

Gnomad4 AMR exome AF: 0.114

Gnomad4 ASJ exome AF: 0.0881

Gnomad4 EAS exome AF: 0.0220

Gnomad4 SAS exome AF: 0.173

Gnomad4 FIN exome AF: 0.151

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.145

GnomAD4 genome AF: 0.257 AC: 38921 AN: 151718 Hom.: 9185 Cov.: 32 AF XY: 0.254 AC XY: 18844 AN XY: 74138

Gnomad4 AFR AF: 0.630

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.0748

Gnomad4 EAS AF: 0.0310

Gnomad4 SAS AF: 0.171

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.210

Alfa AF: 0.123 Hom.: 3334

Bravo AF: 0.268

TwinsUK AF: 0.112 AC: 414

ALSPAC AF: 0.112 AC: 430

ESP6500AA AF: 0.611 AC: 2684

ESP6500EA AF: 0.104 AC: 895

ExAC AF: 0.163 AC: 19787

Asia WGS AF: 0.171 AC: 594 AN: 3478

EpiCase AF: 0.106

EpiControl AF: 0.111

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.13
DEOGEN2	Benign	0.014	T;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.33	.;.;T;T
MetaRNN	Benign	0.0000038	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.3	N;N;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.92	N;N;N;N
REVEL	Benign	0.067
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.83	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.063
MPC		0.34
ClinPred		0.00069	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.059
gMVP		0.14

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: rs8044843; hg19: chr16-67318242; COSMIC: COSV64612563; COSMIC: COSV64612563;