rs117336941

Variant names:

• chr19-40397136-C-T
• rs117336941
• NM_181882.3:c.1216G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_181882.3(PRX):​c.1216G>A​(p.Ala406Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,614,152 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0045 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (45 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.733
• Publications: 7 publications found

Genes affected

PRX (HGNC:13797): (periaxin) This gene encodes a protein involved in peripheral nerve myelin upkeep. The encoded protein contains 2 PDZ domains which were named after PSD95 (post synaptic density protein), DlgA (Drosophila disc large tumor suppressor), and ZO1 (a mammalian tight junction protein). Two alternatively spliced transcript variants have been described for this gene which encode different protein isoforms and which are targeted differently in the Schwann cell. Mutations in this gene cause Charcot-Marie-Tooth neuoropathy, type 4F and Dejerine-Sottas neuropathy. [provided by RefSeq, Jul 2008]

PRX Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 4

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 4F

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease type 3

  Inheritance: AD, AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028489232).
• BP6: Variant 19-40397136-C-T is Benign according to our data. Variant chr19-40397136-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220724.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00445 (678/152330) while in subpopulation NFE AF = 0.00612 (416/68024). AF 95% confidence interval is 0.00563. There are 9 homozygotes in GnomAd4. There are 332 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181882.3. 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
	PRX	NM_181882.3	MANE Select	c.1216G>A	p.Ala406Thr	missense	Exon 7 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.1501G>A	p.Ala501Thr	missense	Exon 7 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.*1421G>A		3_prime_UTR	Exon 6 of 6	NP_066007.1	Q9BXM0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRX	ENST00000324001.8	TSL:1 MANE Select	c.1216G>A	p.Ala406Thr	missense	Exon 7 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.*1421G>A		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000674005.2		c.1501G>A	p.Ala501Thr	missense	Exon 7 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes AF: 0.00445 AC: 678 AN: 152212 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00611

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00451 AC: 1131 AN: 250982 AF XY: 0.00457

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00785

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.00564

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00557 AC: 8136 AN: 1461822 Hom.: 45 Cov.: 36 AF XY: 0.00556 AC XY: 4046 AN XY: 727220

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.000760 AC: 34 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00723 AC: 189 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.0147 AC: 783 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00614 AC: 6830 AN: 1112012

Other (OTH) AF: 0.00429 AC: 259 AN: 60396

GnomAD4 genome AF: 0.00445 AC: 678 AN: 152330 Hom.: 9 Cov.: 33 AF XY: 0.00446 AC XY: 332 AN XY: 74488

African (AFR) AF: 0.00113 AC: 47 AN: 41578

American (AMR) AF: 0.000588 AC: 9 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

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

European-Finnish (FIN) AF: 0.0162 AC: 172 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00612 AC: 416 AN: 68024

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00604 Hom.: 11

Bravo AF: 0.00314

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00674 AC: 58

ExAC AF: 0.00453 AC: 550

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00510

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Charcot-Marie-Tooth disease type 4F (2)
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.20
DANN	Benign	0.63
DEOGEN2	Benign	0.087	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.46	N
PhyloP100		-0.73
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.042
Sift	Benign	0.23	T
Sift4G	Benign	0.10	T
Polyphen		0.0070	B
Vest4		0.13
MVP		0.085
MPC		0.22
ClinPred		0.0021	T
GERP RS		-3.2
Varity_R		0.035
gMVP		0.075
Mutation Taster		=98/2	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: rs117336941; hg19: chr19-40903043;