rs140202670

Variant names:

• chr1-6472613-G-A
• rs140202670
• NM_020631.6:c.994C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-6472613-G-A
• chr1-6472613-G-T

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.994C>T​(p.Arg332Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,611,774 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R332Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 0.839
• Publications: 7 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=0.011217594).
• BP6: Variant 1-6472613-G-A is Benign according to our data. Variant chr1-6472613-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 245662.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00115 (175/152318) while in subpopulation EAS AF = 0.00463 (24/5184). AF 95% confidence interval is 0.00319. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.994C>T	p.Arg332Trp	missense	Exon 10 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.1201C>T	p.Arg401Trp	missense	Exon 10 of 21	NP_001252522.1	A0A804EMX3
	PLEKHG5	NM_001042663.3		c.1105C>T	p.Arg369Trp	missense	Exon 11 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.994C>T	p.Arg332Trp	missense	Exon 10 of 21	ENSP00000366957.3	O94827-5
	PLEKHG5	ENST00000377732.5	TSL:1	c.1105C>T	p.Arg369Trp	missense	Exon 10 of 21	ENSP00000366961.1	O94827-3
	PLEKHG5	ENST00000400915.8	TSL:1	c.1105C>T	p.Arg369Trp	missense	Exon 11 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152200 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00115 AC: 282 AN: 245258 AF XY: 0.00114

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00141

Gnomad EAS exome AF: 0.00347

Gnomad FIN exome AF: 0.0000485

Gnomad NFE exome AF: 0.000913

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00101 AC: 1479 AN: 1459456 Hom.: 4 Cov.: 31 AF XY: 0.00101 AC XY: 736 AN XY: 725868

African (AFR) AF: 0.000209 AC: 7 AN: 33438

American (AMR) AF: 0.00209 AC: 93 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26078

East Asian (EAS) AF: 0.00772 AC: 306 AN: 39620

South Asian (SAS) AF: 0.000513 AC: 44 AN: 85832

European-Finnish (FIN) AF: 0.0000566 AC: 3 AN: 53034

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.000827 AC: 919 AN: 1110856

Other (OTH) AF: 0.00108 AC: 65 AN: 60284

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152318 Hom.: 1 Cov.: 33 AF XY: 0.00130 AC XY: 97 AN XY: 74466

African (AFR) AF: 0.000313 AC: 13 AN: 41580

American (AMR) AF: 0.00360 AC: 55 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68022

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.000973 Hom.: 2

Bravo AF: 0.00128

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000890 AC: 108

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	-	Charcot-Marie-Tooth disease recessive intermediate C (1)
-	-	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	PLEKHG5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.11
Eigen_PC	Benign	-0.070
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.84
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.36
MVP		0.61
MPC		0.92
ClinPred		0.10	T
GERP RS		0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.39
gMVP		0.45
Mutation Taster		=56/44	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: rs140202670; hg19: chr1-6532673; COSMIC: COSV109430084; COSMIC: COSV109430084;