1-6471515-G-C

Variant names:

• chr1-6471515-G-C
• rs139904931
• NM_020631.6:c.1254C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020631.6(PLEKHG5):​c.1254C>G​(p.Pro418Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,610,552 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (24 hom.)
• Consequence: PLEKHG5 NM_020631.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.101
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-6471515-G-C is Benign according to our data. Variant chr1-6471515-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.101 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00397 (604/152258) while in subpopulation NFE AF = 0.00549 (373/67988). AF 95% confidence interval is 0.00503. There are 4 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.1254C>G	p.Pro418Pro	synonymous	Exon 12 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.1461C>G	p.Pro487Pro	synonymous	Exon 12 of 21	NP_001252522.1	A0A804EMX3
	PLEKHG5	NM_001042663.3		c.1365C>G	p.Pro455Pro	synonymous	Exon 13 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.1254C>G	p.Pro418Pro	synonymous	Exon 12 of 21	ENSP00000366957.3	O94827-5
	PLEKHG5	ENST00000377732.5	TSL:1	c.1365C>G	p.Pro455Pro	synonymous	Exon 12 of 21	ENSP00000366961.1	O94827-3
	PLEKHG5	ENST00000400915.8	TSL:1	c.1365C>G	p.Pro455Pro	synonymous	Exon 13 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes AF: 0.00397 AC: 604 AN: 152140 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00753

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00549

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00449 AC: 1051 AN: 234172 AF XY: 0.00451

Gnomad AFR exome AF: 0.000691

Gnomad AMR exome AF: 0.00250

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00724

Gnomad NFE exome AF: 0.00557

Gnomad OTH exome AF: 0.00670

GnomAD4 exome AF: 0.00467 AC: 6814 AN: 1458294 Hom.: 24 Cov.: 33 AF XY: 0.00451 AC XY: 3272 AN XY: 725442

African (AFR) AF: 0.000867 AC: 29 AN: 33430

American (AMR) AF: 0.00249 AC: 111 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.0197 AC: 512 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.000326 AC: 28 AN: 86002

European-Finnish (FIN) AF: 0.00862 AC: 446 AN: 51756

Middle Eastern (MID) AF: 0.000532 AC: 3 AN: 5644

European-Non Finnish (NFE) AF: 0.00485 AC: 5385 AN: 1111050

Other (OTH) AF: 0.00499 AC: 300 AN: 60174

GnomAD4 genome AF: 0.00397 AC: 604 AN: 152258 Hom.: 4 Cov.: 33 AF XY: 0.00383 AC XY: 285 AN XY: 74446

African (AFR) AF: 0.000722 AC: 30 AN: 41554

American (AMR) AF: 0.00274 AC: 42 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00753 AC: 80 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00549 AC: 373 AN: 67988

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00505 Hom.: 1

Bravo AF: 0.00346

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00523

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.7
DANN	Benign	0.82
PhyloP100		0.10
Mutation Taster		=97/3	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: rs139904931; hg19: chr1-6531575; COSMIC: COSV100555923;