6-138095451-T-C

Variant names:

• chr6-138095451-T-C
• rs3734299
• NM_022121.5:c.355+903A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022121.5(PERP):​c.355+903A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 151,918 control chromosomes in the GnomAD database, including 13,152 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.39 (13152 hom., cov: 31)
• Consequence: PERP NM_022121.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.74
• Publications: 4 publications found

Genes affected

PERP (HGNC:17637): (p53 apoptosis effector related to PMP22) Involved in activation of cysteine-type endopeptidase activity. Predicted to be located in plasma membrane. Predicted to be active in cell-cell junction. Implicated in erythrokeratodermia variabilis and mutilating palmoplantar keratoderma with periorificial keratotic plaques. [provided by Alliance of Genome Resources, Apr 2022]

PERP Gene-Disease associations (from GenCC):

• Olmsted syndrome 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• erythrokeratodermia variabilis et progressiva 7

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• mutilating palmoplantar keratoderma with periorificial keratotic plaques

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PERP	NM_022121.5	c.355+903A>G		intron_variant	Intron 2 of 2	ENST00000421351.4	NP_071404.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PERP	ENST00000421351.4	c.355+903A>G		intron_variant	Intron 2 of 2	1	NM_022121.5	ENSP00000397157.2

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59707 AN: 151800 Hom.: 13141 Cov.: 31

Gnomad AFR AF: 0.580

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.0597

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.391

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.393 AC: 59750 AN: 151918 Hom.: 13152 Cov.: 31 AF XY: 0.384 AC XY: 28545 AN XY: 74262

African (AFR) AF: 0.580 AC: 24006 AN: 41384

American (AMR) AF: 0.299 AC: 4569 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1062 AN: 3464

East Asian (EAS) AF: 0.0595 AC: 307 AN: 5160

South Asian (SAS) AF: 0.228 AC: 1100 AN: 4820

European-Finnish (FIN) AF: 0.283 AC: 2983 AN: 10546

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24655 AN: 67950

Other (OTH) AF: 0.386 AC: 813 AN: 2108

Alfa AF: 0.385 Hom.: 3604

Bravo AF: 0.400

Asia WGS AF: 0.178 AC: 619 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0090
DANN	Benign	0.16
PhyloP100		-1.7
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: rs3734299; hg19: chr6-138416588; COSMIC: COSV69827412;