chr20-45512812-C-A

Variant names:

• chr20-45512812-C-A
• rs1176039969
• NM_006652.2:c.109G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00700
• Publications: 0 publications found

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]

ENSG00000237464 (HGNC:):

ACMG classification

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

Sel.	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.: 32

GnomAD2 exomes AF: 0.00000639 AC: 1 AN: 156420 AF XY: 0.0000121

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: 1 AN: 1399326 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 690162

African (AFR) AF: 0.00 AC: 0 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078926

Other (OTH) AF: 0.00 AC: 0 AN: 58004

GnomAD4 genome Cov.: 32

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	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.014
DANN	Benign	0.15
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0072	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.92	T
PhyloP100		-0.0070
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.015
Sift	Benign	0.86	T
Sift4G	Benign	0.87	T
Polyphen		0.13	B
Vest4		0.032
MutPred		0.41		Gain of ubiquitination at K42 (P = 0.0651)
MVP		0.12
ClinPred		0.10	T
GERP RS		-0.94
Varity_R		0.036
gMVP		0.33
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1176039969; hg19: chr20-44141452;