Genetic Variant SPINT4:p.His54Pro (chr20-45723925-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_178455.3(SPINT4):c.161A>C(p.His54Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SPINT4
NM_178455.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.24

Variant links:

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]

SPINT4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINT4	NM_178455.3 link	c.161A>C	p.His54Pro	missense_variant	Exon 2 of 3	ENST00000279058.4	NP_848550.1	Q6UDR6A0A384P5R1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINT4	ENST00000279058.4 link	c.161A>C	p.His54Pro	missense_variant	Exon 2 of 3	1	NM_178455.3	ENSP00000279058.3		Q6UDR6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000416

AC:

AN:

240262

Hom.:

AF XY:

0.00000770

AC XY:

AN XY:

129918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000575

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450872

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721682

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000507

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.161A>C (p.H54P) alteration is located in exon 2 (coding exon 2) of the SPINT4 gene. This alteration results from a A to C substitution at nucleotide position 161, causing the histidine (H) at amino acid position 54 to be replaced by a proline (P). 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

Uncertain

0.37

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.040

Eigen

Benign

-0.072

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.17

M_CAP

Benign

0.023

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.87

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.33

Sift

Benign

0.11

Sift4G

Benign

0.20

Polyphen

1.0

Vest4

0.62

MutPred

0.67

Loss of methylation at R56 (P = 0.0846);

MVP

0.74

MPC

1.1

ClinPred

0.38

GERP RS

3.9

Varity_R

0.83

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over