rs6017667

Variant names:

• chr20-45723981-G-A
• rs6017667
• NM_178455.3:c.217G>A

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 41 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178455.3. 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
	SPINT4	NM_178455.3	MANE Select	c.217G>A	p.Gly73Ser	missense	Exon 2 of 3	NP_848550.1	Q6UDR6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINT4	ENST00000279058.4	TSL:1 MANE Select	c.217G>A	p.Gly73Ser	missense	Exon 2 of 3	ENSP00000279058.3	Q6UDR6

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

GnomAD2 exomes AF: 0.416 AC: 102894 AN: 247122 AF XY: 0.423

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 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

African (AFR) AF: 0.686 AC: 22627 AN: 32988

American (AMR) AF: 0.286 AC: 12485 AN: 43686

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 14234 AN: 26026

East Asian (EAS) AF: 0.461 AC: 18222 AN: 39548

South Asian (SAS) AF: 0.547 AC: 46609 AN: 85180

European-Finnish (FIN) AF: 0.386 AC: 20598 AN: 53344

Middle Eastern (MID) AF: 0.526 AC: 3022 AN: 5748

European-Non Finnish (NFE) AF: 0.363 AC: 403073 AN: 1110434

Other (OTH) AF: 0.430 AC: 25897 AN: 60180

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

African (AFR) AF: 0.673 AC: 27915 AN: 41456

American (AMR) AF: 0.348 AC: 5304 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1855 AN: 3472

East Asian (EAS) AF: 0.490 AC: 2534 AN: 5174

South Asian (SAS) AF: 0.549 AC: 2642 AN: 4812

European-Finnish (FIN) AF: 0.391 AC: 4119 AN: 10534

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.364 AC: 24756 AN: 67920

Other (OTH) AF: 0.470 AC: 989 AN: 2104

Alfa AF: 0.402 Hom.: 54272

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 v4.9

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
PhyloP100		3.9
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
Mutation Taster		=82/18	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6017667; hg19: chr20-44352620; COSMIC: COSV54143262;