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GeneBe

14-94563717-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006215.4(SERPINA4):​c.235C>T​(p.Pro79Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SERPINA4
NM_006215.4 missense

Scores

13
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.47
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SERPINA4NM_006215.4 linkuse as main transcriptc.235C>T p.Pro79Ser missense_variant 2/5 ENST00000557004.6
SERPINA4NM_001289032.2 linkuse as main transcriptc.346C>T p.Pro116Ser missense_variant 2/5
SERPINA4NM_001289033.2 linkuse as main transcriptc.235C>T p.Pro79Ser missense_variant 2/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SERPINA4ENST00000557004.6 linkuse as main transcriptc.235C>T p.Pro79Ser missense_variant 2/51 NM_006215.4 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461640
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727124
Gnomad4 AFR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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 submitterclinical testingAmbry GeneticsJan 03, 2022The c.235C>T (p.P79S) alteration is located in exon 2 (coding exon 1) of the SERPINA4 gene. This alteration results from a C to T substitution at nucleotide position 235, causing the proline (P) at amino acid position 79 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
Uncertain
0.50
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.34
CADD
Uncertain
23
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.83
D;D;D
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.97
D
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.8
M;M;M
MutationTaster
Benign
0.95
D;D;D;D
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-7.9
D;D;D
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.80
MutPred
0.83
Gain of catalytic residue at S78 (P = 5e-04);Gain of catalytic residue at S78 (P = 5e-04);Gain of catalytic residue at S78 (P = 5e-04);
MVP
0.99
MPC
0.34
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.93
gMVP
0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-95030054; COSMIC: COSV105152957; API