19-40394958-C-T

Variant names:

• chr19-40394958-C-T
• rs268674
• NM_181882.3:c.3394G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181882.3(PRX):​c.3394G>A​(p.Gly1132Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.944 in 1,608,036 control chromosomes in the GnomAD database, including 716,680 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1132G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.96 (69595 hom., cov: 32)
  • Exomes 𝑓: 0.94 (647085 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.347
• Publications: 43 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.3784814E-7).
• BP6: Variant 19-40394958-C-T is Benign according to our data. Variant chr19-40394958-C-T is described in ClinVar as Benign. ClinVar VariationId is 130053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

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.3394G>A	p.Gly1132Arg	missense	Exon 7 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.3679G>A	p.Gly1227Arg	missense	Exon 7 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.*3599G>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.3394G>A	p.Gly1132Arg	missense	Exon 7 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.*3599G>A		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000674005.2		c.3679G>A	p.Gly1227Arg	missense	Exon 7 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes AF: 0.956 AC: 145384 AN: 152112 Hom.: 69535 Cov.: 32

Gnomad AFR AF: 0.989

Gnomad AMI AF: 0.866

Gnomad AMR AF: 0.956

Gnomad ASJ AF: 0.954

Gnomad EAS AF: 0.978

Gnomad SAS AF: 0.925

Gnomad FIN AF: 0.943

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.940

Gnomad OTH AF: 0.943

GnomAD2 exomes AF: 0.946 AC: 234284 AN: 247592 AF XY: 0.943

Gnomad AFR exome AF: 0.991

Gnomad AMR exome AF: 0.955

Gnomad ASJ exome AF: 0.944

Gnomad EAS exome AF: 0.979

Gnomad FIN exome AF: 0.941

Gnomad NFE exome AF: 0.940

Gnomad OTH exome AF: 0.938

GnomAD4 exome AF: 0.943 AC: 1372357 AN: 1455806 Hom.: 647085 Cov.: 96 AF XY: 0.941 AC XY: 681552 AN XY: 724130

African (AFR) AF: 0.991 AC: 33152 AN: 33450

American (AMR) AF: 0.955 AC: 42693 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.946 AC: 24719 AN: 26126

East Asian (EAS) AF: 0.981 AC: 38908 AN: 39642

South Asian (SAS) AF: 0.918 AC: 79194 AN: 86240

European-Finnish (FIN) AF: 0.942 AC: 45959 AN: 48784

Middle Eastern (MID) AF: 0.908 AC: 5232 AN: 5762

European-Non Finnish (NFE) AF: 0.941 AC: 1045475 AN: 1110838

Other (OTH) AF: 0.946 AC: 57025 AN: 60274

GnomAD4 genome AF: 0.956 AC: 145502 AN: 152230 Hom.: 69595 Cov.: 32 AF XY: 0.956 AC XY: 71110 AN XY: 74420

African (AFR) AF: 0.989 AC: 41123 AN: 41560

American (AMR) AF: 0.956 AC: 14627 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.954 AC: 3311 AN: 3472

East Asian (EAS) AF: 0.978 AC: 5030 AN: 5144

South Asian (SAS) AF: 0.925 AC: 4458 AN: 4822

European-Finnish (FIN) AF: 0.943 AC: 9999 AN: 10600

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.940 AC: 63910 AN: 68012

Other (OTH) AF: 0.944 AC: 1995 AN: 2114

Alfa AF: 0.943 Hom.: 132429

Bravo AF: 0.958

TwinsUK AF: 0.944 AC: 3499

ALSPAC AF: 0.949 AC: 3656

ESP6500AA AF: 0.989 AC: 4358

ESP6500EA AF: 0.936 AC: 8047

ExAC AF: 0.947 AC: 114939

Asia WGS AF: 0.956 AC: 3325 AN: 3478

EpiCase AF: 0.926

EpiControl AF: 0.932

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Charcot-Marie-Tooth disease type 4F (2)
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Dejerine-Sottas disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.69
DEOGEN2	Benign	0.076	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0081	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	9.4e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.63	N
PhyloP100		-0.35
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.79	N
REVEL	Benign	0.036
Sift	Benign	0.13	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.018
MutPred		0.43		Gain of solvent accessibility (P = 0.0097)
MPC		0.27
ClinPred		0.0036	T
GERP RS		3.6
Varity_R		0.050
gMVP		0.078
Mutation Taster		=100/0	polymorphism (auto)

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: rs268674; hg19: chr19-40900865; COSMIC: COSV52526409; COSMIC: COSV52526409;