15-40844915-T-A

Variant names:

• chr15-40844915-T-A
• rs148755059
• NM_003710.4:c.361T>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP3 BP4_Moderate

The NM_003710.4(SPINT1):​c.361T>A​(p.Cys121Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: SPINT1 NM_003710.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.95

Genes affected

SPINT1 (HGNC:11246): (serine peptidase inhibitor, Kunitz type 1) The protein encoded by this gene is a member of the Kunitz family of serine protease inhibitors. The protein is a potent inhibitor specific for HGF activator and is thought to be involved in the regulation of the proteolytic activation of HGF in injured tissues. Alternative splicing results in multiple variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.118717164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINT1	NM_003710.4	c.361T>A	p.Cys121Ser	missense_variant	Exon 2 of 11	ENST00000562057.6	NP_003701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINT1	ENST00000562057.6	c.361T>A	p.Cys121Ser	missense_variant	Exon 2 of 11	1	NM_003710.4	ENSP00000457076.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000336 AC: 84 AN: 249878 Hom.: 0 AF XY: 0.000222 AC XY: 30 AN XY: 135304

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00726

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000712

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000214 AC: 313 AN: 1461734 Hom.: 0 Cov.: 31 AF XY: 0.000188 AC XY: 137 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00807

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74316

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000599 Hom.: 0

Bravo AF: 0.000242

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.361T>A (p.C121S) alteration is located in exon 2 (coding exon 1) of the SPINT1 gene. This alteration results from a T to A substitution at nucleotide position 361, causing the cysteine (C) at amino acid position 121 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;T;T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.0	M;M;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.6	D;D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.96
MutPred		0.92		Loss of catalytic residue at L122 (P = 0.0135);Loss of catalytic residue at L122 (P = 0.0135);Loss of catalytic residue at L122 (P = 0.0135);.;
MVP		0.76
MPC		0.82
ClinPred		0.47	T
GERP RS		5.3
Varity_R		0.99
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148755059; hg19: chr15-41137113;