rs199794578

Variant names:

• chr1-6473327-T-A
• rs199794578
• NM_020631.6:c.719A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-6473327-T-A
• chr1-6473327-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020631.6(PLEKHG5):​c.719A>T​(p.Asp240Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000709 in 1,409,618 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D240G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.65
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3794206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.719A>T	p.Asp240Val	missense_variant	Exon 8 of 21	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.719A>T	p.Asp240Val	missense_variant	Exon 8 of 21	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1409618 Hom.: 0 Cov.: 34 AF XY: 0.00000144 AC XY: 1 AN XY: 696722

African (AFR) AF: 0.00 AC: 0 AN: 31988

American (AMR) AF: 0.00 AC: 0 AN: 36902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25260

East Asian (EAS) AF: 0.00 AC: 0 AN: 36434

South Asian (SAS) AF: 0.00 AC: 0 AN: 80524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1086206

Other (OTH) AF: 0.00 AC: 0 AN: 58396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	.;.;.;.;.;.;.;.;D;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;D;D;D;D;.;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.8	.;.;.;.;.;.;.;.;L;.
PhyloP100		5.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.021	D;D;D;D;D;D;D;D;D;T
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D
Polyphen		0.99, 0.97, 0.95	.;.;.;.;D;D;.;.;P;P
Vest4		0.34
MutPred		0.20		.;.;.;.;.;.;.;.;Loss of ubiquitination at K299 (P = 0.0184);.;
MVP		0.76
MPC		0.72
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.30
gMVP		0.68
Mutation Taster		=70/30	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: rs199794578; hg19: chr1-6533387;