chr19-40394506-C-T

Variant names:

• chr19-40394506-C-T
• rs143289108
• NM_181882.3:c.3846G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_181882.3(PRX):​c.3846G>A​(p.Ser1282Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 1,599,890 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1282S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (4 hom.)
• Consequence: PRX NM_181882.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -9.10
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 (BayesDel_noAF=-0.9).
• BP6: Variant 19-40394506-C-T is Benign according to our data. Variant chr19-40394506-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 329253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0026 (396/152278) while in subpopulation AFR AF = 0.00922 (383/41560). AF 95% confidence interval is 0.00845. There are 2 homozygotes in GnomAd4. There are 208 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.3846G>A	p.Ser1282Ser	synonymous	Exon 7 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.4131G>A	p.Ser1377Ser	synonymous	Exon 7 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.*4051G>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.3846G>A	p.Ser1282Ser	synonymous	Exon 7 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.*4051G>A		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000674005.2		c.4131G>A	p.Ser1377Ser	synonymous	Exon 7 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 388 AN: 152160 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00905

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000620 AC: 137 AN: 221088 AF XY: 0.000456

Gnomad AFR exome AF: 0.00888

Gnomad AMR exome AF: 0.000313

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000182

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000408

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000240 AC: 348 AN: 1447612 Hom.: 4 Cov.: 33 AF XY: 0.000189 AC XY: 136 AN XY: 719490

African (AFR) AF: 0.00858 AC: 284 AN: 33086

American (AMR) AF: 0.000256 AC: 11 AN: 42930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25782

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38772

South Asian (SAS) AF: 0.0000237 AC: 2 AN: 84476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51124

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5752

European-Non Finnish (NFE) AF: 0.00000633 AC: 7 AN: 1105900

Other (OTH) AF: 0.000686 AC: 41 AN: 59790

GnomAD4 genome AF: 0.00260 AC: 396 AN: 152278 Hom.: 2 Cov.: 33 AF XY: 0.00279 AC XY: 208 AN XY: 74448

African (AFR) AF: 0.00922 AC: 383 AN: 41560

American (AMR) AF: 0.000523 AC: 8 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67994

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00189 Hom.: 1

Bravo AF: 0.00297

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.11
DANN	Benign	0.80
PhyloP100		-9.1
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: rs143289108; hg19: chr19-40900413; COSMIC: COSV105871286; COSMIC: COSV105871286;