chr1-6470758-C-A

Variant names:

• chr1-6470758-C-A
• rs868002197
• NM_020631.6:c.1519G>T

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.1519G>T​(p.Ala507Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,410,024 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. A507P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.266
• 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: 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=0.11170006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.1519G>T	p.Ala507Ser	missense_variant	Exon 14 of 21	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.1519G>T	p.Ala507Ser	missense_variant	Exon 14 of 21	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000117 AC: 2 AN: 171048 AF XY: 0.0000218

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: 0.0000142

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1410024 Hom.: 0 Cov.: 35 AF XY: 0.00000287 AC XY: 2 AN XY: 697350

⚠️ 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: 32314

American (AMR) AF: 0.00 AC: 0 AN: 37490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25322

East Asian (EAS) AF: 0.00 AC: 0 AN: 36874

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46166

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

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1087022

Other (OTH) AF: 0.00 AC: 0 AN: 58522

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000410 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.064	.;.;.;.;.;.;.;.;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.76	T;.;T;T;T;T;.;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	.;.;.;.;.;.;.;.;L;.
PhyloP100		0.27
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.56	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.010
Sift	Benign	0.49	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.33	T;T;T;T;T;T;T;T;T;T
Polyphen		0.21, 0.063, 0.25, 0.048	.;.;.;.;B;B;.;.;B;B
Vest4		0.26
MutPred		0.35		.;.;.;.;.;.;.;.;Gain of phosphorylation at A563 (P = 0.0248);.;
MVP		0.24
MPC		0.35
ClinPred		0.054	T
GERP RS		-0.41
Varity_R		0.039
gMVP		0.63
Mutation Taster		=94/6	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: rs868002197; hg19: chr1-6530818;