1-6474072-C-T

Variant names:

• chr1-6474072-C-T
• rs143484278
• NM_020631.6:c.532G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020631.6(PLEKHG5):​c.532G>A​(p.Gly178Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,612,446 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G178G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.02
• Publications: 3 publications found

Genes affected

PLEKHG5 (HGNC:29105): (pleckstrin homology and RhoGEF domain containing G5) This gene encodes a protein that activates the nuclear factor kappa B (NFKB1) signaling pathway. Mutations in this gene are associated with autosomal recessive distal spinal muscular atrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

PLEKHG5 Gene-Disease associations (from GenCC):

• neuromuscular disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease recessive intermediate C

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• neuronopathy, distal hereditary motor, autosomal recessive 4

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054044127).
• BP6: Variant 1-6474072-C-T is Benign according to our data. Variant chr1-6474072-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 297971.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00123 (188/152302) while in subpopulation NFE AF = 0.00128 (87/68000). AF 95% confidence interval is 0.00106. There are 0 homozygotes in GnomAd4. There are 106 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020631.6. 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
	PLEKHG5	NM_020631.6	MANE Select	c.532G>A	p.Gly178Arg	missense	Exon 7 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.739G>A	p.Gly247Arg	missense	Exon 7 of 21	NP_001252522.1	A0A804EMX3
	PLEKHG5	NM_001042663.3		c.643G>A	p.Gly215Arg	missense	Exon 8 of 22	NP_001036128.2	O94827-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	ENST00000377728.8	TSL:2 MANE Select	c.532G>A	p.Gly178Arg	missense	Exon 7 of 21	ENSP00000366957.3	O94827-5
	PLEKHG5	ENST00000377732.5	TSL:1	c.643G>A	p.Gly215Arg	missense	Exon 7 of 21	ENSP00000366961.1	O94827-3
	PLEKHG5	ENST00000400915.8	TSL:1	c.643G>A	p.Gly215Arg	missense	Exon 8 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00127 AC: 313 AN: 245906 AF XY: 0.00115

Gnomad AFR exome AF: 0.0000644

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000219

Gnomad FIN exome AF: 0.00686

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00106 AC: 1542 AN: 1460144 Hom.: 4 Cov.: 38 AF XY: 0.000998 AC XY: 725 AN XY: 726328

African (AFR) AF: 0.000209 AC: 7 AN: 33448

American (AMR) AF: 0.000201 AC: 9 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39664

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86080

European-Finnish (FIN) AF: 0.00820 AC: 431 AN: 52588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.000914 AC: 1016 AN: 1111582

Other (OTH) AF: 0.000862 AC: 52 AN: 60298

GnomAD4 genome AF: 0.00123 AC: 188 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74472

African (AFR) AF: 0.000168 AC: 7 AN: 41578

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00753 AC: 80 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 68000

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000967 Hom.: 0

Bravo AF: 0.000559

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00126 AC: 153

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000891

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	Neuronopathy, distal hereditary motor, autosomal recessive 4 (1)
-	-	1	Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C (1)
-	-	1	not provided (1)
-	-	1	PLEKHG5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.035
Sift	Benign	0.052	T
Sift4G	Uncertain	0.043	D
Polyphen		0.099	B
Vest4		0.18
MutPred		0.37		Gain of solvent accessibility (P = 0.0016)
MVP		0.22
MPC		0.31
ClinPred		0.015	T
GERP RS		2.9
Varity_R		0.056
gMVP		0.23
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143484278; hg19: chr1-6534132;