1-6473333-G-C

Variant names:

• chr1-6473333-G-C
• rs61741379
• NM_020631.6:c.713C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001265593.2(PLEKHG5):​c.920C>G​(p.Thr307Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,558,310 control chromosomes in the GnomAD database, including 30,376 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (9579 hom., cov: 34)
  • Exomes 𝑓: 0.15 (20797 hom.)
• Consequence: PLEKHG5 NM_001265593.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.854
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.980708E-6).
• BP6: Variant 1-6473333-G-C is Benign according to our data. Variant chr1-6473333-G-C is described in ClinVar as Benign. ClinVar VariationId is 198895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	NM_020631.6	MANE Select	c.713C>G	p.Thr238Ser	missense	Exon 8 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.920C>G	p.Thr307Ser	missense	Exon 8 of 21	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.824C>G	p.Thr275Ser	missense	Exon 9 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.713C>G	p.Thr238Ser	missense	Exon 8 of 21	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.824C>G	p.Thr275Ser	missense	Exon 8 of 21	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.824C>G	p.Thr275Ser	missense	Exon 9 of 22	ENSP00000383706.4

Frequencies

GnomAD3 genomes AF: 0.276 AC: 42074 AN: 152180 Hom.: 9529 Cov.: 34

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.00730

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.158 AC: 25070 AN: 158834 AF XY: 0.153

Gnomad AFR exome AF: 0.645

Gnomad AMR exome AF: 0.0990

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.00716

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.149 AC: 209913 AN: 1406012 Hom.: 20797 Cov.: 36 AF XY: 0.149 AC XY: 103376 AN XY: 694512

African (AFR) AF: 0.656 AC: 20887 AN: 31852

American (AMR) AF: 0.108 AC: 3965 AN: 36568

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3514 AN: 25228

East Asian (EAS) AF: 0.00908 AC: 329 AN: 36244

South Asian (SAS) AF: 0.163 AC: 13054 AN: 80182

European-Finnish (FIN) AF: 0.165 AC: 7935 AN: 47994

Middle Eastern (MID) AF: 0.218 AC: 1222 AN: 5604

European-Non Finnish (NFE) AF: 0.138 AC: 149113 AN: 1084058

Other (OTH) AF: 0.170 AC: 9894 AN: 58282

GnomAD4 genome AF: 0.277 AC: 42183 AN: 152298 Hom.: 9579 Cov.: 34 AF XY: 0.274 AC XY: 20383 AN XY: 74478

African (AFR) AF: 0.632 AC: 26249 AN: 41542

American (AMR) AF: 0.163 AC: 2500 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 472 AN: 3472

East Asian (EAS) AF: 0.00732 AC: 38 AN: 5192

South Asian (SAS) AF: 0.168 AC: 811 AN: 4832

European-Finnish (FIN) AF: 0.157 AC: 1666 AN: 10620

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9732 AN: 68010

Other (OTH) AF: 0.237 AC: 501 AN: 2114

Alfa AF: 0.179 Hom.: 1184

Bravo AF: 0.291

TwinsUK AF: 0.131 AC: 487

ALSPAC AF: 0.132 AC: 508

ESP6500AA AF: 0.557 AC: 2342

ESP6500EA AF: 0.128 AC: 1057

ExAC AF: 0.128 AC: 13680

Asia WGS AF: 0.143 AC: 495 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	3.3
DANN	Benign	0.12
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00094	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0000070	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.85
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.81	N
REVEL	Benign	0.072
Sift	Benign	0.97	T
Sift4G	Benign	0.95	T
Polyphen		0.0	B
Vest4		0.042
MutPred		0.15		Gain of glycosylation at T294 (P = 0.043)
MPC		0.23
ClinPred		0.0011	T
GERP RS		0.98
Varity_R		0.034
gMVP		0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61741379; hg19: chr1-6533393; COSMIC: COSV61700195; COSMIC: COSV61700195;