Genetic Variant NM_006215.4:c.343T>C (chr14-94563825-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006215.4(SERPINA4):c.343T>C(p.Ser115Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. S115T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SERPINA4
NM_006215.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.68

Publications

0 publications found

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:

ENSG00000294537 (HGNC:):

ENSG00000294537 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07046947).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006215.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPINA4	NM_006215.4	MANE Select	c.343T>C	p.Ser115Pro	missense	Exon 2 of 5	NP_006206.2
SERPINA4	NM_001289032.2		c.454T>C	p.Ser152Pro	missense	Exon 2 of 5	NP_001275961.1
SERPINA4	NM_001289033.2		c.343T>C	p.Ser115Pro	missense	Exon 2 of 5	NP_001275962.1	P29622

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPINA4	ENST00000557004.6	TSL:1 MANE Select	c.343T>C	p.Ser115Pro	missense	Exon 2 of 5	ENSP00000450838.1	P29622
SERPINA4	ENST00000298841.5	TSL:1	c.343T>C	p.Ser115Pro	missense	Exon 2 of 5	ENSP00000298841.5	P29622
SERPINA4	ENST00000555095.5	TSL:1	c.343T>C	p.Ser115Pro	missense	Exon 2 of 5	ENSP00000451172.1	P29622

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.21

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.28

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.074

M_CAP

Benign

0.029

MetaRNN

Benign

0.070

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.72

PhyloP100

-2.7

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.76

REVEL

Benign

0.21

Sift

Benign

0.38

Sift4G

Benign

0.34

Polyphen

0.0010

Vest4

0.086

MutPred

0.52

Loss of stability (P = 0.0472)

MVP

0.44

MPC

0.060

ClinPred

0.065

GERP RS

-8.8

Varity_R

0.27

gMVP

0.43

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over