NM_020631.6:c.440-6A>G

Variant names:

• chr1-6474170-T-C
• rs202049535
• NM_020631.6:c.440-6A>G

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.440-6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000836 in 1,613,232 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (9 hom.)
• Consequence: PLEKHG5 NM_020631.6 splice_region, intron
• Scores: Splicing: ADA: 0.00008048
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.553
• 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: 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 (BayesDel_noAF=-0.86).
• BP6: Variant 1-6474170-T-C is Benign according to our data. Variant chr1-6474170-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00405 (617/152304) while in subpopulation AFR AF = 0.0141 (587/41566). AF 95% confidence interval is 0.0132. There are 8 homozygotes in GnomAd4. There are 312 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.440-6A>G		splice_region intron	N/A	NP_065682.2
	PLEKHG5	NM_001265593.2		c.647-6A>G		splice_region intron	N/A	NP_001252522.1	A0A804EMX3
	PLEKHG5	NM_001042663.3		c.551-6A>G		splice_region intron	N/A	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.440-6A>G		splice_region intron	N/A	ENSP00000366957.3	O94827-5
	PLEKHG5	ENST00000377732.5	TSL:1	c.551-6A>G		splice_region intron	N/A	ENSP00000366961.1	O94827-3
	PLEKHG5	ENST00000400915.8	TSL:1	c.551-6A>G		splice_region intron	N/A	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 618 AN: 152186 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.000992 AC: 247 AN: 248916 AF XY: 0.000806

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000500 AC: 731 AN: 1460928 Hom.: 9 Cov.: 38 AF XY: 0.000462 AC XY: 336 AN XY: 726730

African (AFR) AF: 0.0174 AC: 581 AN: 33476

American (AMR) AF: 0.000693 AC: 31 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

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

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52678

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5758

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111922

Other (OTH) AF: 0.00123 AC: 74 AN: 60364

GnomAD4 genome AF: 0.00405 AC: 617 AN: 152304 Hom.: 8 Cov.: 33 AF XY: 0.00419 AC XY: 312 AN XY: 74474

African (AFR) AF: 0.0141 AC: 587 AN: 41566

American (AMR) AF: 0.00111 AC: 17 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00219 Hom.: 2

Bravo AF: 0.00492

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	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	-0.86
CADD	Benign	1.6
DANN	Benign	0.81
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000080
dbscSNV1_RF	Benign	0.026
SpliceAI score (max)		0.15		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: rs202049535; hg19: chr1-6534230;