rs145856805

Variant names:

• chr19-40396316-C-A
• rs145856805
• NM_181882.3:c.2036G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-40396316-C-A
• chr19-40396316-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_181882.3(PRX):​c.2036G>T​(p.Arg679Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,605,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R679Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.99
• Publications: 2 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), Orphanet, Ambry Genetics
• Charcot-Marie-Tooth disease type 3

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07864249).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRX	NM_181882.3	c.2036G>T	p.Arg679Leu	missense_variant	Exon 7 of 7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.2321G>T	p.Arg774Leu	missense_variant	Exon 7 of 7		NP_001398056.1
PRX	XM_017027047.2	c.1934G>T	p.Arg645Leu	missense_variant	Exon 4 of 4		XP_016882536.1
PRX	NM_020956.2	c.*2241G>T		3_prime_UTR_variant	Exon 6 of 6		NP_066007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8	c.2036G>T	p.Arg679Leu	missense_variant	Exon 7 of 7	1	NM_181882.3	ENSP00000326018.6

Frequencies

GnomAD3 genomes AF: 0.00000691 AC: 1 AN: 144778 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460974 Hom.: 0 Cov.: 37 AF XY: 0.0000138 AC XY: 10 AN XY: 726828

African (AFR) AF: 0.00 AC: 0 AN: 32860

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111930

Other (OTH) AF: 0.00 AC: 0 AN: 60314

GnomAD4 genome AF: 0.00000691 AC: 1 AN: 144778 Hom.: 0 Cov.: 32 AF XY: 0.0000142 AC XY: 1 AN XY: 70276

African (AFR) AF: 0.00 AC: 0 AN: 38320

American (AMR) AF: 0.00 AC: 0 AN: 14284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.00 AC: 0 AN: 4874

South Asian (SAS) AF: 0.00 AC: 0 AN: 4582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66846

Other (OTH) AF: 0.00 AC: 0 AN: 1982

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.32
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L
PhyloP100		-3.0
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.041
Sift	Benign	0.14	T
Sift4G	Benign	0.083	T
Polyphen		0.0010	B
Vest4		0.27
MutPred		0.29		Loss of solvent accessibility (P = 0.0606);
MVP		0.27
MPC		0.28
ClinPred		0.23	T
GERP RS		-4.7
Varity_R		0.076
gMVP		0.23
Mutation Taster		=99/1	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: rs145856805; hg19: chr19-40902223;