NM_020631.6:c.713C>A

Variant names:

• chr1-6473333-G-T
• rs61741379
• NM_020631.6:c.713C>A

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.713C>A​(p.Thr238Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. T238S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.854
• 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: 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: 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=0.044389546).

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.713C>A	p.Thr238Asn	missense	Exon 8 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.920C>A	p.Thr307Asn	missense	Exon 8 of 21	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.824C>A	p.Thr275Asn	missense	Exon 9 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.713C>A	p.Thr238Asn	missense	Exon 8 of 21	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.824C>A	p.Thr275Asn	missense	Exon 8 of 21	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.824C>A	p.Thr275Asn	missense	Exon 9 of 22	ENSP00000383706.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406160 Hom.: 0 Cov.: 36 AF XY: 0.00000144 AC XY: 1 AN XY: 694592

African (AFR) AF: 0.00 AC: 0 AN: 31856

American (AMR) AF: 0.00 AC: 0 AN: 36570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25228

East Asian (EAS) AF: 0.00 AC: 0 AN: 36246

South Asian (SAS) AF: 0.00 AC: 0 AN: 80190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084174

Other (OTH) AF: 0.00 AC: 0 AN: 58284

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.27
DEOGEN2	Benign	0.053	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.85
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.031
Sift	Benign	0.49	T
Sift4G	Benign	0.098	T
Polyphen		0.0050	B
Vest4		0.070
MutPred		0.13		Loss of phosphorylation at T294 (P = 0.0296)
MVP		0.076
MPC		0.29
ClinPred		0.083	T
GERP RS		0.98
Varity_R		0.038
gMVP		0.32
Mutation Taster		=92/8	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: rs61741379; hg19: chr1-6533393;