rs144750655

Variant names:

• chr1-6474166-T-C
• rs144750655
• NM_020631.6:c.440-2A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PVS1_Moderate PP5 BS1_Supporting

The NM_001265593.2(PLEKHG5):​c.647-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00047 in 1,613,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: PLEKHG5 NM_001265593.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9192
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:2
• Conservation: PhyloP100: -2.05
• Publications: 3 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 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04708798 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.6, offset of -39, new splice context is: gggaccccctcctccaccAGacc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 1-6474166-T-C is Pathogenic according to our data. Variant chr1-6474166-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 423836.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000492 (719/1461024) while in subpopulation NFE AF = 0.000621 (691/1111940). AF 95% confidence interval is 0.000583. There are 0 homozygotes in GnomAdExome4. There are 337 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001265593.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	NM_020631.6	MANE Select	c.440-2A>G		splice_acceptor intron	N/A	NP_065682.2
	PLEKHG5	NM_001265593.2		c.647-2A>G		splice_acceptor intron	N/A	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.551-2A>G		splice_acceptor intron	N/A	NP_001036128.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	ENST00000377728.8	TSL:2 MANE Select	c.440-2A>G		splice_acceptor intron	N/A	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.551-2A>G		splice_acceptor intron	N/A	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.551-2A>G		splice_acceptor intron	N/A	ENSP00000383706.4

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000165 AC: 41 AN: 249072 AF XY: 0.000163

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000276

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000492 AC: 719 AN: 1461024 Hom.: 0 Cov.: 38 AF XY: 0.000464 AC XY: 337 AN XY: 726802

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.000157 AC: 7 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86220

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52730

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.000621 AC: 691 AN: 1111940

Other (OTH) AF: 0.000199 AC: 12 AN: 60372

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74462

African (AFR) AF: 0.000120 AC: 5 AN: 41560

American (AMR) AF: 0.000327 AC: 5 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000299 Hom.: 0

Bravo AF: 0.000268

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000190 AC: 23

EpiCase AF: 0.000327

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	-	-	Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C (4)
2	1	-	not provided (3)
-	1	-	Inborn genetic diseases (1)
1	-	-	Neuronopathy, distal hereditary motor, autosomal recessive 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Benign	-1.0
CADD	Benign	16
DANN	Benign	0.33
Eigen	Benign	-0.78
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.010	N
PhyloP100		-2.0
GERP RS		-4.9
Mutation Taster		=89/11	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Benign	0.28
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.89		Position offset: -8
DS_AL_spliceai		0.97		Position offset: -2

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

Other links and lift over

dbSNP: rs144750655; hg19: chr1-6534226; COSMIC: COSV109429993; COSMIC: COSV109429993;