1-6470312-G-C

Position:

• chr1-6470312-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020631.6(PLEKHG5):​c.1724C>G​(p.Pro575Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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. P575L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.55

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11508259).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG5	NM_020631.6	c.1724C>G	p.Pro575Arg	missense_variant	16/21	ENST00000377728.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.1724C>G	p.Pro575Arg	missense_variant	16/21	2	NM_020631.6	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.60
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;.;D;D;D;D;.;D;D;D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.75	D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.088
Sift	Benign	0.17	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T;T;T;T;T;T
Polyphen		0.13, 0.063, 0.10, 0.012	.;.;.;.;B;B;.;.;B;B
Vest4		0.44
MutPred		0.30		.;.;.;.;.;.;.;.;Gain of solvent accessibility (P = 0.0411);.;
MVP		0.15
MPC		0.39
ClinPred		0.63	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs77134982; hg19: chr1-6530372;