chr1-6470770-C-A

Variant names:

• chr1-6470770-C-A
• rs868161574
• NM_020631.6:c.1507G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_020631.6(PLEKHG5):​c.1507G>T​(p.Glu503*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000707 in 1,414,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.1507G>T	p.Glu503*	stop_gained	Exon 14 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.1714G>T	p.Glu572*	stop_gained	Exon 14 of 21	NP_001252522.1	A0A804EMX3
	PLEKHG5	NM_001042663.3		c.1618G>T	p.Glu540*	stop_gained	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.1507G>T	p.Glu503*	stop_gained	Exon 14 of 21	ENSP00000366957.3	O94827-5
	PLEKHG5	ENST00000377732.5	TSL:1	c.1618G>T	p.Glu540*	stop_gained	Exon 14 of 21	ENSP00000366961.1	O94827-3
	PLEKHG5	ENST00000400915.8	TSL:1	c.1618G>T	p.Glu540*	stop_gained	Exon 15 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414238 Hom.: 0 Cov.: 35 AF XY: 0.00000143 AC XY: 1 AN XY: 699738

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32444

American (AMR) AF: 0.00 AC: 0 AN: 37886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25378

East Asian (EAS) AF: 0.0000269 AC: 1 AN: 37178

South Asian (SAS) AF: 0.00 AC: 0 AN: 80916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088954

Other (OTH) AF: 0.00 AC: 0 AN: 58672

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000203 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.1
Vest4		0.41
GERP RS		4.7
Mutation Taster		=5/195	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs868161574; hg19: chr1-6530830;