rs1405069

chr6-36954908-A-Cchr6-36954908-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_153370.3(PI16):c.148A>C(p.Thr50Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 1,612,844 control chromosomes in the GnomAD database, including 176,539 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.53 (22417 hom., cov: 31)
  • Exomes 𝑓: 0.46 (154122 hom.)
• Consequence: PI16 NM_153370.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.389

Genes affected

PI16 (HGNC:21245): (peptidase inhibitor 16) Predicted to enable peptidase inhibitor activity. Predicted to be involved in negative regulation of peptidase activity. Predicted to act upstream of or within negative regulation of cell growth involved in cardiac muscle cell development. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.6780249E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PI16	NM_153370.3	c.148A>C	p.Thr50Pro	missense_variant	1/7	ENST00000373674.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PI16	ENST00000373674.4	c.148A>C	p.Thr50Pro	missense_variant	1/7	1	NM_153370.3	P1
PI16	ENST00000611814.4	c.148A>C	p.Thr50Pro	missense_variant	2/8	5		P1
PI16	ENST00000647861.1	c.148A>C	p.Thr50Pro	missense_variant	3/9			P1

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80257 AN: 151800 Hom.: 22373 Cov.: 31

Gnomad AFR AF: 0.702

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.480

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.425

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.508

GnomAD3 exomes AF: 0.478 AC: 118591 AN: 248036 Hom.: 29409 AF XY: 0.465 AC XY: 62551 AN XY: 134394

Gnomad AFR exome AF: 0.707

Gnomad AMR exome AF: 0.607

Gnomad ASJ exome AF: 0.406

Gnomad EAS exome AF: 0.466

Gnomad SAS exome AF: 0.394

Gnomad FIN exome AF: 0.427

Gnomad NFE exome AF: 0.447

Gnomad OTH exome AF: 0.472

GnomAD4 exome AF: 0.455 AC: 665095 AN: 1460926 Hom.: 154122 Cov.: 52 AF XY: 0.452 AC XY: 328609 AN XY: 726776

Gnomad4 AFR exome AF: 0.713

Gnomad4 AMR exome AF: 0.601

Gnomad4 ASJ exome AF: 0.409

Gnomad4 EAS exome AF: 0.508

Gnomad4 SAS exome AF: 0.398

Gnomad4 FIN exome AF: 0.425

Gnomad4 NFE exome AF: 0.446

Gnomad4 OTH exome AF: 0.464

GnomAD4 genome AF: 0.529 AC: 80360 AN: 151918 Hom.: 22417 Cov.: 31 AF XY: 0.526 AC XY: 39074 AN XY: 74242

Gnomad4 AFR AF: 0.703

Gnomad4 AMR AF: 0.584

Gnomad4 ASJ AF: 0.388

Gnomad4 EAS AF: 0.480

Gnomad4 SAS AF: 0.401

Gnomad4 FIN AF: 0.425

Gnomad4 NFE AF: 0.448

Gnomad4 OTH AF: 0.504

Alfa AF: 0.462 Hom.: 34751

Bravo AF: 0.552

TwinsUK AF: 0.454 AC: 1685

ALSPAC AF: 0.436 AC: 1682

ESP6500AA AF: 0.693 AC: 3052

ESP6500EA AF: 0.446 AC: 3833

ExAC AF: 0.473 AC: 57480

Asia WGS AF: 0.410 AC: 1426 AN: 3478

EpiCase AF: 0.446

EpiControl AF: 0.454

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.034
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.85
Dann	Benign	0.14
DEOGEN2	Benign	0.00043	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0024	N
MetaRNN	Benign	0.0000027	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.3	N;N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.38	T
Polyphen		0.0	B;B;B
Vest4		0.064, 0.047
MPC		0.40
ClinPred		0.0020	T
GERP RS		3.7
Varity_R		0.075
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1405069; hg19: chr6-36922684; COSMIC: COSV65448502;