chr6-138096400-C-A

Position:

• chr6-138096400-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022121.5(PERP):​c.309G>T​(p.Gln103His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PERP NM_022121.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.527

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37441242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PERP	NM_022121.5	c.309G>T	p.Gln103His	missense_variant	2/3	ENST00000421351.4	NP_071404.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PERP	ENST00000421351.4	c.309G>T	p.Gln103His	missense_variant	2/3	1	NM_022121.5	ENSP00000397157	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.309G>T (p.Q103H) alteration is located in exon 2 (coding exon 2) of the PERP gene. This alteration results from a G to T substitution at nucleotide position 309, causing the glutamine (Q) at amino acid position 103 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.97	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.31
Sift	Benign	0.10	T
Sift4G	Benign	0.14	T
Polyphen		0.99	D
Vest4		0.28
MutPred		0.32		Gain of catalytic residue at L105 (P = 0.0584);
MVP		0.69
MPC		1.3
ClinPred		0.79	D
GERP RS		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.099
gMVP		0.42

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-138417537;