NM_020631.6:c.1535T>A

Variant names:

• chr1-6470742-A-T
• rs548243654
• NM_020631.6:c.1535T>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_020631.6(PLEKHG5):​c.1535T>A​(p.Val512Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000068 in 1,558,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V512A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000067 (1 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.12
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026712775).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000788 (12/152300) while in subpopulation SAS AF = 0.00207 (10/4828). AF 95% confidence interval is 0.00112. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.1535T>A	p.Val512Asp	missense	Exon 14 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.1742T>A	p.Val581Asp	missense	Exon 14 of 21	NP_001252522.1	A0A804EMX3
	PLEKHG5	NM_001042663.3		c.1646T>A	p.Val549Asp	missense	Exon 15 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.1535T>A	p.Val512Asp	missense	Exon 14 of 21	ENSP00000366957.3	O94827-5
	PLEKHG5	ENST00000377732.5	TSL:1	c.1646T>A	p.Val549Asp	missense	Exon 14 of 21	ENSP00000366961.1	O94827-3
	PLEKHG5	ENST00000400915.8	TSL:1	c.1646T>A	p.Val549Asp	missense	Exon 15 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000150 AC: 25 AN: 167010 AF XY: 0.000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000291

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000668 AC: 94 AN: 1406452 Hom.: 1 Cov.: 35 AF XY: 0.0000892 AC XY: 62 AN XY: 695302

African (AFR) AF: 0.00 AC: 0 AN: 32194

American (AMR) AF: 0.00 AC: 0 AN: 37102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25276

East Asian (EAS) AF: 0.00 AC: 0 AN: 36576

South Asian (SAS) AF: 0.000996 AC: 80 AN: 80320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1085508

Other (OTH) AF: 0.000205 AC: 12 AN: 58414

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74492

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

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

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

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000848 AC: 10

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.77
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.58	N
PhyloP100		1.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.15
Sift	Benign	0.28	T
Sift4G	Uncertain	0.012	D
Polyphen		0.55	P
Vest4		0.52
MutPred		0.44		Gain of disorder (P = 0.0399)
MVP		0.25
MPC		1.1
ClinPred		0.041	T
GERP RS		2.4
Varity_R		0.16
gMVP		0.71
Mutation Taster		=85/15	polymorphism

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: rs548243654; hg19: chr1-6530802;