rs117505788

Variant names:

• chr1-6475089-A-G
• rs117505788
• NM_020631.6:c.260T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020631.6(PLEKHG5):​c.260T>C​(p.Ile87Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00142 in 1,612,190 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I87F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (31 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.86
• Publications: 6 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• neuronopathy, distal hereditary motor, autosomal recessive 4

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026628375).
• BP6: Variant 1-6475089-A-G is Benign according to our data. Variant chr1-6475089-A-G is described in ClinVar as Benign. ClinVar VariationId is 297975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00181 (276/152184) while in subpopulation EAS AF = 0.0442 (228/5160). AF 95% confidence interval is 0.0395. There are 2 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020631.6. 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.260T>C	p.Ile87Thr	missense	Exon 5 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.467T>C	p.Ile156Thr	missense	Exon 5 of 21	NP_001252522.1	A0A804EMX3
	PLEKHG5	NM_001042663.3		c.371T>C	p.Ile124Thr	missense	Exon 6 of 22	NP_001036128.2	O94827-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	ENST00000377728.8	TSL:2 MANE Select	c.260T>C	p.Ile87Thr	missense	Exon 5 of 21	ENSP00000366957.3	O94827-5
	PLEKHG5	ENST00000377732.5	TSL:1	c.371T>C	p.Ile124Thr	missense	Exon 5 of 21	ENSP00000366961.1	O94827-3
	PLEKHG5	ENST00000400915.8	TSL:1	c.371T>C	p.Ile124Thr	missense	Exon 6 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 276 AN: 152066 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.0441

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00384 AC: 965 AN: 251482 AF XY: 0.00366

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.0468

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00138 AC: 2015 AN: 1460006 Hom.: 31 Cov.: 30 AF XY: 0.00137 AC XY: 997 AN XY: 726476

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00567 AC: 148 AN: 26120

East Asian (EAS) AF: 0.0412 AC: 1635 AN: 39686

South Asian (SAS) AF: 0.000905 AC: 78 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1110346

Other (OTH) AF: 0.00179 AC: 108 AN: 60328

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152184 Hom.: 2 Cov.: 31 AF XY: 0.00199 AC XY: 148 AN XY: 74422

African (AFR) AF: 0.0000241 AC: 1 AN: 41522

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.0442 AC: 228 AN: 5160

South Asian (SAS) AF: 0.00229 AC: 11 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00213 Hom.: 20

Bravo AF: 0.00256

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00360 AC: 437

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.20
Sift	Benign	0.037	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.85	P
Vest4		0.56
MVP		0.63
MPC		0.37
ClinPred		0.044	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.19
Mutation Taster		=100/0	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: rs117505788; hg19: chr1-6535149; COSMIC: COSV61700027; COSMIC: COSV61700027;