1-6473088-G-C

Variant names:

• chr1-6473088-G-C
• NM_020631.6:c.882C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020631.6(PLEKHG5):​c.882C>G​(p.Phe294Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F294F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.690

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41650617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.882C>G	p.Phe294Leu	missense_variant	Exon 9 of 21	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.882C>G	p.Phe294Leu	missense_variant	Exon 9 of 21	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461674 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	.;.;.;.;.;.;.;.;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.93	D;.;D;D;D;D;.;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Benign	2.0	.;.;.;.;.;.;.;.;M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;.;D;D;.;.;D;D
Vest4		0.68
MutPred		0.26		.;.;.;.;.;.;.;.;Gain of disorder (P = 0.1185);.;
MVP		0.25
MPC		0.93
ClinPred		0.99	D
GERP RS		-8.8
Varity_R		0.27
gMVP		0.74

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-6533148;