rs706107

Positions:

• chr9-33240227-G-A

Variant summary

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

The ENST00000379721.4(SPINK4):​c.19G>A​(p.Val7Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,604,088 control chromosomes in the GnomAD database, including 59,568 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 0.35 (12043 hom., cov: 32)
  • Exomes 𝑓: 0.25 (47525 hom.)
• Consequence: SPINK4 ENST00000379721.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.657

Genes affected

SPINK4 (HGNC:16646): (serine peptidase inhibitor Kazal type 4) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity and response to xenobiotic stimulus. Predicted to be located in extracellular region. [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=3.861092E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK4	NM_014471.3	c.19G>A	p.Val7Ile	missense_variant	1/4	ENST00000379721.4	NP_055286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK4	ENST00000379721.4	c.19G>A	p.Val7Ile	missense_variant	1/4	1	NM_014471.3	ENSP00000369045	P1
SPINK4	ENST00000379725.5	c.131-4885G>A		intron_variant		3		ENSP00000369048

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53584 AN: 151964 Hom.: 12034 Cov.: 32

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.332

GnomAD3 exomes AF: 0.261 AC: 61843 AN: 237184 Hom.: 9259 AF XY: 0.252 AC XY: 32344 AN XY: 128274

Gnomad AFR exome AF: 0.645

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.245

Gnomad SAS exome AF: 0.254

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.246 AC: 357443 AN: 1452006 Hom.: 47525 Cov.: 32 AF XY: 0.245 AC XY: 177141 AN XY: 721830

Gnomad4 AFR exome AF: 0.664

Gnomad4 AMR exome AF: 0.252

Gnomad4 ASJ exome AF: 0.225

Gnomad4 EAS exome AF: 0.282

Gnomad4 SAS exome AF: 0.254

Gnomad4 FIN exome AF: 0.227

Gnomad4 NFE exome AF: 0.232

Gnomad4 OTH exome AF: 0.269

GnomAD4 genome AF: 0.353 AC: 53641 AN: 152082 Hom.: 12043 Cov.: 32 AF XY: 0.347 AC XY: 25819 AN XY: 74364

Gnomad4 AFR AF: 0.643

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.256

Gnomad4 SAS AF: 0.277

Gnomad4 FIN AF: 0.220

Gnomad4 NFE AF: 0.232

Gnomad4 OTH AF: 0.330

Alfa AF: 0.254 Hom.: 14101

Bravo AF: 0.371

TwinsUK AF: 0.224 AC: 830

ALSPAC AF: 0.230 AC: 888

ESP6500AA AF: 0.643 AC: 2832

ESP6500EA AF: 0.234 AC: 2010

ExAC AF: 0.268 AC: 32458

Asia WGS AF: 0.325 AC: 1131 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.29
DANN	Benign	0.57
DEOGEN2	Benign	0.0087	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0000039	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.051
Sift	Benign	0.22	T
Sift4G	Benign	0.18	T
Polyphen		0.010	B
Vest4		0.062
MPC		0.063
ClinPred		0.0020	T
GERP RS		-7.2
Varity_R		0.023
gMVP		0.13

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

Other links and lift over

dbSNP: rs706107; hg19: chr9-33240225; COSMIC: COSV65687838;