rs149715830

Variant names:

• chr19-40396778-A-G
• rs149715830
• NM_181882.3:c.1574T>C
• PRX p.Val525Ala

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.1574T>C​(p.Val525Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00082 in 1,608,936 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V525V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (2 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:7
• Conservation: PhyloP100: 0.743
• Publications: 5 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: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.01118499).
• BP6: Variant 19-40396778-A-G is Benign according to our data. Variant chr19-40396778-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242179.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00128 (195/151954) while in subpopulation NFE AF = 0.00252 (171/67956). AF 95% confidence interval is 0.00221. There are 0 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD 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.1574T>C	p.Val525Ala	missense	Exon 7 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.1859T>C	p.Val620Ala	missense	Exon 7 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.*1779T>C		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.1574T>C	p.Val525Ala	missense	Exon 7 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.*1779T>C		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000674005.2		c.1859T>C	p.Val620Ala	missense	Exon 7 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 151838 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000473

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00252

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000570 AC: 143 AN: 250708 AF XY: 0.000560

Gnomad AFR exome AF: 0.000311

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000772 AC: 1125 AN: 1456982 Hom.: 2 Cov.: 36 AF XY: 0.000851 AC XY: 617 AN XY: 724740

African (AFR) AF: 0.000120 AC: 4 AN: 33422

American (AMR) AF: 0.000114 AC: 5 AN: 44010

Ashkenazi Jewish (ASJ) AF: 0.000422 AC: 11 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85670

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000944 AC: 1047 AN: 1108892

Other (OTH) AF: 0.000581 AC: 35 AN: 60252

GnomAD4 genome AF: 0.00128 AC: 195 AN: 151954 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74292

African (AFR) AF: 0.000266 AC: 11 AN: 41424

American (AMR) AF: 0.000327 AC: 5 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.000473 AC: 5 AN: 10572

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

European-Non Finnish (NFE) AF: 0.00252 AC: 171 AN: 67956

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

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00114

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	4	not provided (8)
-	1	1	Charcot-Marie-Tooth disease (2)
-	1	1	not specified (2)
-	1	-	Charcot-Marie-Tooth disease type 4 (1)
-	1	-	Charcot-Marie-Tooth disease type 4F (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.4
DANN	Benign	0.17
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.74
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.063
Sift	Benign	0.61	T
Sift4G	Benign	0.78	T
Varity_R		0.050
gMVP		0.11
Mutation Taster		=93/7	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs149715830;

hg19: chr19-40902685;

COSMIC: COSV106092369;