1-6477534-G-C

Variant names:

• chr1-6477534-G-C
• rs776271244
• NM_020631.6:c.38C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020631.6(PLEKHG5):​c.38C>G​(p.Pro13Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,400 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P13L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.71

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.38C>G	p.Pro13Arg	missense_variant	Exon 2 of 21	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.38C>G	p.Pro13Arg	missense_variant	Exon 2 of 21	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249226 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134934

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459400 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;.;.;.;.;.;.;.;D;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;D;.;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.8	.;.;.;.;.;.;.;.;L;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	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	.;.;.;.;D;D;.;.;D;D
Vest4		0.65
MutPred		0.32		.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0034);.;
MVP		0.87
MPC		0.54
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.50
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs776271244; hg19: chr1-6537594;