Genetic Variant PLEKHG5:c.24+4054A>G (chr1-6492439-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000377732.5(PLEKHG5):c.24+4054A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 151,964 control chromosomes in the GnomAD database, including 11,264 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 11264 hom., cov: 32)

Consequence

PLEKHG5
ENST00000377732.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0670

Publications

8 publications found

Variant links:

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

PLEKHG5 links:

ENSG00000299237 (HGNC:):

ENSG00000299237 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
PLEKHG5	NM_001042663.3 link	c.24+4054A>G	intron_variant	Intron 2 of 21	NP_001036128.2	O94827-3
PLEKHG5	NM_001265592.2 link	c.24+4054A>G	intron_variant	Intron 2 of 21	NP_001252521.2	O94827-3
PLEKHG5	NM_198681.4 link	c.-88+4054A>G	intron_variant	Intron 2 of 21	NP_941374.3	O94827-5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
PLEKHG5	ENST00000377732.5 link	c.24+4054A>G	intron_variant	Intron 1 of 20	1	ENSP00000366961.1	O94827-3
PLEKHG5	ENST00000400915.8 link	c.24+4054A>G	intron_variant	Intron 2 of 21	1	ENSP00000383706.4	O94827-3
PLEKHG5	ENST00000377740.5 link	c.-88+4054A>G	intron_variant	Intron 2 of 21	1	ENSP00000366969.4	O94827-5Q5SY18

Frequencies

GnomAD3 genomes

AF:

0.297

AC:

45037

AN:

151846

Hom.:

11203

Cov.:

show subpopulations

Gnomad AFR

AF:

0.686

Gnomad AMI

AF:

0.0976

Gnomad AMR

AF:

0.187

Gnomad ASJ

AF:

0.158

Gnomad EAS

AF:

0.298

Gnomad SAS

AF:

0.220

Gnomad FIN

AF:

0.169

Gnomad MID

AF:

0.258

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.254

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.297

AC:

45162

AN:

151964

Hom.:

11264

Cov.:

AF XY:

0.298

AC XY:

22114

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.686

AC:

28418

AN:

41404

American (AMR)

AF:

0.187

AC:

2849

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.158

AC:

547

AN:

3468

East Asian (EAS)

AF:

0.298

AC:

1536

AN:

5156

South Asian (SAS)

AF:

0.220

AC:

1058

AN:

4812

European-Finnish (FIN)

AF:

0.169

AC:

1786

AN:

10588

Middle Eastern (MID)

AF:

0.267

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.122

AC:

8263

AN:

67956

Other (OTH)

AF:

0.256

AC:

538

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1149

2299

3448

4598

5747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

384

768

1152

1536

1920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.183

Hom.:

5968

Bravo

AF:

0.315

Asia WGS

AF:

0.320

AC:

1111

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

4.2

(source)

DANN

Benign

0.55

PhyloP100

-0.067

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over