rs367543633

Variant names:

• chr1-6473408-G-A
• rs367543633
• NM_020631.6:c.638C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-6473408-G-A
• chr1-6473408-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020631.6(PLEKHG5):​c.638C>T​(p.Ala213Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000583 in 1,543,180 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A213A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000060 (1 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.551
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01996842).

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.638C>T	p.Ala213Val	missense	Exon 8 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.845C>T	p.Ala282Val	missense	Exon 8 of 21	NP_001252522.1	A0A804EMX3
	PLEKHG5	NM_001042663.3		c.749C>T	p.Ala250Val	missense	Exon 9 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.638C>T	p.Ala213Val	missense	Exon 8 of 21	ENSP00000366957.3	O94827-5
	PLEKHG5	ENST00000377732.5	TSL:1	c.749C>T	p.Ala250Val	missense	Exon 8 of 21	ENSP00000366961.1	O94827-3
	PLEKHG5	ENST00000400915.8	TSL:1	c.749C>T	p.Ala250Val	missense	Exon 9 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152228 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000141 AC: 2 AN: 141926 AF XY: 0.0000263

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: 0.0000388

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000604 AC: 84 AN: 1390952 Hom.: 1 Cov.: 35 AF XY: 0.0000759 AC XY: 52 AN XY: 685298

African (AFR) AF: 0.0000635 AC: 2 AN: 31482

American (AMR) AF: 0.00 AC: 0 AN: 35442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25012

East Asian (EAS) AF: 0.00 AC: 0 AN: 35614

South Asian (SAS) AF: 0.00 AC: 0 AN: 78960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5488

European-Non Finnish (NFE) AF: 0.0000707 AC: 76 AN: 1075614

Other (OTH) AF: 0.000104 AC: 6 AN: 57664

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152228 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74360

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000567 Hom.: 0

Bravo AF: 0.0000529

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000129 AC: 1

ExAC AF: 0.0000129 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.55
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.022
Sift	Benign	0.087	T
Sift4G	Benign	0.33	T
Polyphen		0.046	B
Vest4		0.071
MVP		0.072
MPC		0.26
ClinPred		0.017	T
GERP RS		0.70
Varity_R		0.021
gMVP		0.50
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs367543633; hg19: chr1-6533468;