1-6474063-C-T

Variant names:

• chr1-6474063-C-T
• rs527341275
• NM_020631.6:c.541G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_020631.6(PLEKHG5):​c.541G>A​(p.Ala181Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000975 in 1,610,212 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A181P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.301
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059225857).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000118 (18/151908) while in subpopulation SAS AF = 0.00146 (7/4800). AF 95% confidence interval is 0.000684. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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_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.541G>A	p.Ala181Thr	missense	Exon 7 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.748G>A	p.Ala250Thr	missense	Exon 7 of 21	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.652G>A	p.Ala218Thr	missense	Exon 8 of 22	NP_001036128.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	ENST00000377728.8	TSL:2 MANE Select	c.541G>A	p.Ala181Thr	missense	Exon 7 of 21	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.652G>A	p.Ala218Thr	missense	Exon 7 of 21	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.652G>A	p.Ala218Thr	missense	Exon 8 of 22	ENSP00000383706.4

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151790 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000205 AC: 50 AN: 243374 AF XY: 0.000226

Gnomad AFR exome AF: 0.000267

Gnomad AMR exome AF: 0.0000877

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.000477

Gnomad NFE exome AF: 0.0000642

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000953 AC: 139 AN: 1458304 Hom.: 0 Cov.: 38 AF XY: 0.000119 AC XY: 86 AN XY: 725366

African (AFR) AF: 0.000269 AC: 9 AN: 33398

American (AMR) AF: 0.000112 AC: 5 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39560

South Asian (SAS) AF: 0.000895 AC: 77 AN: 86032

European-Finnish (FIN) AF: 0.000345 AC: 18 AN: 52178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1110640

Other (OTH) AF: 0.000116 AC: 7 AN: 60180

GnomAD4 genome AF: 0.000118 AC: 18 AN: 151908 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74294

African (AFR) AF: 0.0000965 AC: 4 AN: 41466

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

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

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.00146 AC: 7 AN: 4800

European-Finnish (FIN) AF: 0.000190 AC: 2 AN: 10528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67886

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000140 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.000215 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	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	0.066
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.7
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.30
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.022
Sift	Benign	0.11	T
Sift4G	Uncertain	0.039	D
Polyphen		0.046	B
Vest4		0.059
MVP		0.16
MPC		0.25
ClinPred		0.015	T
GERP RS		-0.64
Varity_R		0.038
gMVP		0.20
Mutation Taster		=95/5	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: rs527341275; hg19: chr1-6534123;