Genetic Variant SPINK9:p.Leu12Met (chr5-148335647-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001040433.2(SPINK9):c.34C>A(p.Leu12Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SPINK9
NM_001040433.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.104

Variant links:

Genes affected

SPINK9 (HGNC:32951): (serine peptidase inhibitor Kazal type 9) The protein encoded by this gene is a Kazal-type serine protease inhibitor that appears to specifically target kallikrein-related peptidase 5 (KLK5) in the palmo-plantar epidermis. KLK5 is an important initiator of skin desquamation, so the encoded protease inhibitor may regulate skin differentiation in the palms of hands and soles of feet. This cationic protein has also been shown to promote keratinocyte migration by activation of the epidermal growth factor receptor (EGFR). [provided by RefSeq, Dec 2015]

SPINK9 links:

FBXO38-DT (HGNC:55589): (FBXO38 divergent transcript)

FBXO38-DT links:

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ACMG classification

Classification made for transcript

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=0.29811034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK9	NM_001040433.2 link	c.34C>A	p.Leu12Met	missense_variant	Exon 1 of 4	ENST00000377906.2	NP_001035523.1	Q5DT21
SPINK9	XM_017009709.2 link	c.119-775C>A		intron_variant	Intron 1 of 3		XP_016865198.1	D6RJC5
FBXO38-DT	NR_105057.1 link	n.497-27482G>T		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK9	ENST00000377906.2 link	c.34C>A	p.Leu12Met	missense_variant	Exon 1 of 4	1	NM_001040433.2	ENSP00000367139.1		Q5DT21

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251160

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461382

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727032

show subpopulations

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000285

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34C>A (p.L12M) alteration is located in exon 1 (coding exon 1) of the SPINK9 gene. This alteration results from a C to A substitution at nucleotide position 34, causing the leucine (L) at amino acid position 12 to be replaced by a methionine (M). 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

Benign

0.10

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.013

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.33

M_CAP

Benign

0.0093

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.90

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.59

REVEL

Benign

0.15

Sift

Benign

0.071

Sift4G

Uncertain

0.025

Polyphen

1.0

Vest4

0.39

MVP

0.48

MPC

0.12

ClinPred

0.81

GERP RS

2.5

Varity_R

0.11

gMVP

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over