1-6470570-G-C

Variant names:

• chr1-6470570-G-C
• rs370515061
• NM_020631.6:c.1616C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020631.6(PLEKHG5):​c.1616C>G​(p.Ala539Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A539V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.95
• Publications: 2 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• neuronopathy, distal hereditary motor, autosomal recessive 4

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.088480085).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	NM_020631.6	MANE Select	c.1616C>G	p.Ala539Gly	missense	Exon 15 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.1823C>G	p.Ala608Gly	missense	Exon 15 of 21	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.1727C>G	p.Ala576Gly	missense	Exon 16 of 22	NP_001036128.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	ENST00000377728.8	TSL:2 MANE Select	c.1616C>G	p.Ala539Gly	missense	Exon 15 of 21	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.1727C>G	p.Ala576Gly	missense	Exon 15 of 21	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.1727C>G	p.Ala576Gly	missense	Exon 16 of 22	ENSP00000383706.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0043	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.9
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.21
Sift	Benign	0.064	T
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.43		Loss of stability (P = 0.0382)
MVP		0.69
MPC		0.91
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.22
gMVP		0.80
Mutation Taster		=69/31	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: rs370515061; hg19: chr1-6530630;