1-6469659-G-T

Position:

• chr1-6469659-G-T

Variant summary

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

The NM_020631.6(PLEKHG5):​c.1818C>A​(p.Phe606Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,052 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F606F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.14

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG5	NM_020631.6	c.1818C>A	p.Phe606Leu	missense_variant	17/21	ENST00000377728.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.1818C>A	p.Phe606Leu	missense_variant	17/21	2	NM_020631.6	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250510 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135488

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461052 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4 AN XY: 726826

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Benign	-0.033
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D;.;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.18	T;T;T;T;T;T;T;T;T;T
Sift4G	Uncertain	0.034	D;D;D;D;D;D;D;D;D;D
Polyphen		0.96, 0.93, 0.12	.;.;.;.;D;D;.;.;P;B
Vest4		0.79
MutPred		0.51		.;.;.;.;.;.;.;.;Gain of catalytic residue at F662 (P = 0.0761);.;
MVP		0.50
MPC		0.93
ClinPred		0.91	D
GERP RS		2.8
Varity_R		0.27
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs149147021; hg19: chr1-6529719;