rs6017667

Positions:

• chr20-45723981-G-A

Variant summary

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

The NM_178455.3(SPINT4):​c.217G>A​(p.Gly73Ser) variant causes a missense change. The variant allele was found at a frequency of 0.396 in 1,609,072 control chromosomes in the GnomAD database, including 134,996 homozygotes. In-silico tool predicts 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 0.46 (18001 hom., cov: 31)
  • Exomes 𝑓: 0.39 (116995 hom.)
• Consequence: SPINT4 NM_178455.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.93

Genes affected

SPINT4 (HGNC:16130): (serine peptidase inhibitor, Kunitz type 4) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. 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=2.9414892E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINT4	NM_178455.3	c.217G>A	p.Gly73Ser	missense_variant	2/3	ENST00000279058.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINT4	ENST00000279058.4	c.217G>A	p.Gly73Ser	missense_variant	2/3	1	NM_178455.3	P1

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70430 AN: 151820 Hom.: 17980 Cov.: 31

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.472

GnomAD3 exomes AF: 0.416 AC: 102894 AN: 247122 Hom.: 23188 AF XY: 0.423 AC XY: 56523 AN XY: 133574

Gnomad AFR exome AF: 0.670

Gnomad AMR exome AF: 0.277

Gnomad ASJ exome AF: 0.554

Gnomad EAS exome AF: 0.491

Gnomad SAS exome AF: 0.547

Gnomad FIN exome AF: 0.397

Gnomad NFE exome AF: 0.367

Gnomad OTH exome AF: 0.420

GnomAD4 exome AF: 0.389 AC: 566767 AN: 1457134 Hom.: 116995 Cov.: 38 AF XY: 0.395 AC XY: 285950 AN XY: 724840

Gnomad4 AFR exome AF: 0.686

Gnomad4 AMR exome AF: 0.286

Gnomad4 ASJ exome AF: 0.547

Gnomad4 EAS exome AF: 0.461

Gnomad4 SAS exome AF: 0.547

Gnomad4 FIN exome AF: 0.386

Gnomad4 NFE exome AF: 0.363

Gnomad4 OTH exome AF: 0.430

GnomAD4 genome AF: 0.464 AC: 70489 AN: 151938 Hom.: 18001 Cov.: 31 AF XY: 0.465 AC XY: 34548 AN XY: 74258

Gnomad4 AFR AF: 0.673

Gnomad4 AMR AF: 0.348

Gnomad4 ASJ AF: 0.534

Gnomad4 EAS AF: 0.490

Gnomad4 SAS AF: 0.549

Gnomad4 FIN AF: 0.391

Gnomad4 NFE AF: 0.364

Gnomad4 OTH AF: 0.470

Alfa AF: 0.396 Hom.: 26534

Bravo AF: 0.468

TwinsUK AF: 0.374 AC: 1385

ALSPAC AF: 0.363 AC: 1400

ESP6500AA AF: 0.641 AC: 2825

ESP6500EA AF: 0.375 AC: 3223

ExAC AF: 0.426 AC: 51725

Asia WGS AF: 0.495 AC: 1723 AN: 3478

EpiCase AF: 0.383

EpiControl AF: 0.385

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.00029	T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	0.30	P
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MPC		0.87
ClinPred		0.037	T
GERP RS		4.5
Varity_R		0.89
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs6017667; hg19: chr20-44352620; COSMIC: COSV54143262;