rs61730399

Variant names:

• chr1-6473042-C-T
• rs61730399
• NM_020631.6:c.928G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020631.6(PLEKHG5):​c.928G>A​(p.Asp310Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,614,058 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (12 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 3.47
• Publications: 10 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036782324).
• BP6: Variant 1-6473042-C-T is Benign according to our data. Variant chr1-6473042-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 297961.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00236 (359/152332) while in subpopulation AMR AF = 0.00536 (82/15312). AF 95% confidence interval is 0.00442. There are 0 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	NM_020631.6	MANE Select	c.928G>A	p.Asp310Asn	missense	Exon 9 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.1135G>A	p.Asp379Asn	missense	Exon 9 of 21	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.1039G>A	p.Asp347Asn	missense	Exon 10 of 22	NP_001036128.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	ENST00000377728.8	TSL:2 MANE Select	c.928G>A	p.Asp310Asn	missense	Exon 9 of 21	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.1039G>A	p.Asp347Asn	missense	Exon 9 of 21	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.1039G>A	p.Asp347Asn	missense	Exon 10 of 22	ENSP00000383706.4

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00257 AC: 644 AN: 250440 AF XY: 0.00243

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00618

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00240

Gnomad NFE exome AF: 0.00355

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00288 AC: 4207 AN: 1461726 Hom.: 12 Cov.: 34 AF XY: 0.00272 AC XY: 1976 AN XY: 727144

African (AFR) AF: 0.000418 AC: 14 AN: 33478

American (AMR) AF: 0.00248 AC: 111 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00658 AC: 172 AN: 26136

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

South Asian (SAS) AF: 0.000475 AC: 41 AN: 86250

European-Finnish (FIN) AF: 0.00274 AC: 146 AN: 53294

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00320 AC: 3554 AN: 1111984

Other (OTH) AF: 0.00268 AC: 162 AN: 60392

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.00252 AC XY: 188 AN XY: 74484

African (AFR) AF: 0.000697 AC: 29 AN: 41582

American (AMR) AF: 0.00536 AC: 82 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00285 AC: 194 AN: 68018

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00263 Hom.: 5

Bravo AF: 0.00237

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00260 AC: 316

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00326

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	-	1	Inborn genetic diseases (1)
-	-	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 specified (1)
-	-	1	PLEKHG5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.075
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.040	D
Polyphen		0.73	P
Vest4		0.43
MVP		0.59
MPC		0.72
ClinPred		0.029	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.066
gMVP		0.25
Mutation Taster		=98/2	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: rs61730399; hg19: chr1-6533102; COSMIC: COSV104652048; COSMIC: COSV104652048;