1-6467765-G-T

Variant names:

• chr1-6467765-G-T
• rs45463998
• NM_020631.6:c.3011+60C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020631.6(PLEKHG5):​c.3011+60C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,585,026 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (18 hom., cov: 33)
  • Exomes 𝑓: 0.00079 (11 hom.)
• Consequence: PLEKHG5 NM_020631.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.62
• 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: 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-6467765-G-T is Benign according to our data. Variant chr1-6467765-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1198764.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00742 (1130/152346) while in subpopulation AFR AF = 0.0251 (1045/41584). AF 95% confidence interval is 0.0239. There are 18 homozygotes in GnomAd4. There are 562 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.3011+60C>A		intron_variant	Intron 20 of 20	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.3011+60C>A		intron_variant	Intron 20 of 20	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1114 AN: 152228 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.0100

GnomAD4 exome AF: 0.000794 AC: 1137 AN: 1432680 Hom.: 11 Cov.: 26 AF XY: 0.000644 AC XY: 460 AN XY: 713998

African (AFR) AF: 0.0277 AC: 911 AN: 32858

American (AMR) AF: 0.00111 AC: 49 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39398

South Asian (SAS) AF: 0.0000938 AC: 8 AN: 85314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51988

Middle Eastern (MID) AF: 0.000547 AC: 3 AN: 5484

European-Non Finnish (NFE) AF: 0.0000110 AC: 12 AN: 1088070

Other (OTH) AF: 0.00260 AC: 154 AN: 59326

GnomAD4 genome AF: 0.00742 AC: 1130 AN: 152346 Hom.: 18 Cov.: 33 AF XY: 0.00755 AC XY: 562 AN XY: 74484

African (AFR) AF: 0.0251 AC: 1045 AN: 41584

American (AMR) AF: 0.00385 AC: 59 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.0000701 Hom.: 0

Bravo AF: 0.00871

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 15, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.68
PhyloP100		-1.6
Mutation Taster		=100/0	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: rs45463998; hg19: chr1-6527825;