11-394491-G-T

Variant names:

• chr11-394491-G-T
• rs373142275
• NM_007183.4:c.199G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007183.4(PKP3):​c.199G>T​(p.Ala67Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,259,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A67T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PKP3 NM_007183.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0370
• Publications: 0 publications found

Genes affected

PKP3 (HGNC:9025): (plakophilin 3) This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This protein may act in cellular desmosome-dependent adhesion and signaling pathways. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.078686476).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007183.4. 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
	PKP3	NM_007183.4	MANE Select	c.199G>T	p.Ala67Ser	missense	Exon 1 of 13	NP_009114.1	Q9Y446-1
	PKP3	NM_001303029.2		c.244G>T	p.Ala82Ser	missense	Exon 2 of 14	NP_001289958.1	Q9Y446-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP3	ENST00000331563.7	TSL:1 MANE Select	c.199G>T	p.Ala67Ser	missense	Exon 1 of 13	ENSP00000331678.2	Q9Y446-1
	PKP3	ENST00000534401.6	TSL:3	c.244G>T	p.Ala82Ser	missense	Exon 2 of 14	ENSP00000434517.3	Q9Y446-2
	PKP3	ENST00000895790.1		c.199G>T	p.Ala67Ser	missense	Exon 1 of 13	ENSP00000565849.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000151 AC: 19 AN: 1259274 Hom.: 0 Cov.: 31 AF XY: 0.0000146 AC XY: 9 AN XY: 614784

African (AFR) AF: 0.00 AC: 0 AN: 24474

American (AMR) AF: 0.00 AC: 0 AN: 15366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19216

East Asian (EAS) AF: 0.0000351 AC: 1 AN: 28488

South Asian (SAS) AF: 0.00 AC: 0 AN: 62520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3702

European-Non Finnish (NFE) AF: 0.0000166 AC: 17 AN: 1022362

Other (OTH) AF: 0.0000192 AC: 1 AN: 51958

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.3
DANN	Benign	0.73
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.20	N
PhyloP100		0.037
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.13
Sift	Benign	0.69	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.052
MutPred		0.17		Gain of loop (P = 0.0013)
MVP		0.41
MPC		0.064
ClinPred		0.018	T
GERP RS		0.088
PromoterAI		0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.043
gMVP		0.23
Mutation Taster		=95/5	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: rs373142275; hg19: chr11-394491;