dbSNP rs1176039969: SPINT3:p.Ala37Ser (chr20-45512812-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006652.2(SPINT3):c.109G>T(p.Ala37Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A37T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SPINT3
NM_006652.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00700

Publications

0 publications found

Variant links:

Genes affected

SPINT3 (HGNC:11248): (serine peptidase inhibitor, Kunitz type 3) Predicted to enable receptor antagonist activity and transforming growth factor beta binding activity. Predicted to be involved in negative regulation of transforming growth factor beta receptor signaling pathway. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

SPINT3 links:

ENSG00000237464 (HGNC:):

ENSG00000237464 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.050094336).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006652.2. 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
	SPINT3	NM_006652.2	MANE Select	c.109G>T	p.Ala37Ser	missense	Exon 2 of 2	NP_006643.1	P49223

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPINT3	ENST00000217428.7	TSL:1 MANE Select	c.109G>T	p.Ala37Ser	missense	Exon 2 of 2	ENSP00000217428.6	P49223
ENSG00000237464	ENST00000803561.1		n.120-20462C>A		intron	N/A
ENSG00000237464	ENST00000803562.1		n.127-20462C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000639

AC:

AN:

156420

AF XY:

0.0000121

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000165

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399326

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690162

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31590

American (AMR)

AF:

0.00

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1078926

Other (OTH)

AF:

0.00

AC:

AN:

58004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.014

(source)

DANN

Benign

0.15

DEOGEN2

Benign

0.0016

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0072

LIST_S2

Benign

0.15

M_CAP

Benign

0.0049

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.92

PhyloP100

-0.0070

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.46

REVEL

Benign

0.015

Sift

Benign

0.86

Sift4G

Benign

0.87

Polyphen

0.13

Vest4

0.032

MutPred

0.41

Gain of ubiquitination at K42 (P = 0.0651)

MVP

0.12

ClinPred

0.10

GERP RS

-0.94

Varity_R

0.036

gMVP

0.33

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.20

Position offset: 32

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over