Variant 14-94563892-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006215.4(SERPINA4):c.410C>A(p.Thr137Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

SERPINA4
NM_006215.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.885

Variant links:

Genes affected

SERPINA4 (HGNC:8948): (serpin family A member 4) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Located in extracellular exosome. Biomarker of diabetic retinopathy. [provided by Alliance of Genome Resources, Apr 2022]

SERPINA4 links:

SERPINA5 (HGNC:8723): (serpin family A member 5) The protein encoded by this gene is a member of the serpin family of proteins, a group of proteins that inhibit serine proteases. This gene is one in a cluster of serpin genes located on the q arm of chromosome 14. This family member is a glycoprotein that can inhibit several serine proteases, including protein C and various plasminogen activators and kallikreins, and it thus plays diverse roles in hemostasis and thrombosis in multiple organs. [provided by RefSeq, Aug 2012]

SERPINA5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3608151).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SERPINA4	NM_006215.4 linkuse as main transcript	c.410C>A	p.Thr137Lys	missense_variant	2/5	ENST00000557004.6
SERPINA4	NM_001289032.2 linkuse as main transcript	c.521C>A	p.Thr174Lys	missense_variant	2/5
SERPINA4	NM_001289033.2 linkuse as main transcript	c.410C>A	p.Thr137Lys	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA4	ENST00000557004.6 linkuse as main transcript	c.410C>A	p.Thr137Lys	missense_variant	2/5	1	NM_006215.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000994

AC:

AN:

251436

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000385

AC:

563

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000359

AC XY:

261

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000480

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000164

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000186

Hom.:

Bravo

AF:

0.000147

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2022

The c.410C>A (p.T137K) alteration is located in exon 2 (coding exon 1) of the SERPINA4 gene. This alteration results from a C to A substitution at nucleotide position 410, causing the threonine (T) at amino acid position 137 to be replaced by a lysine (K). 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

Benign

0.21

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.22

CADD

Benign

5.4

DANN

Benign

0.89

DEOGEN2

Uncertain

0.43

T;T;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.12

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.36

T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

1.6

L;L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.7

N;N;N

REVEL

Uncertain

0.44

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

0.81

P;P;P

Vest4

0.37

MVP

0.77

MPC

0.24

ClinPred

0.087

GERP RS

-2.8

Varity_R

0.51

gMVP

0.60

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