14-94614593-C-A

Position:

• chr14-94614593-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001085.5(SERPINA3):​c.152C>A​(p.Ser51Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINA3 NM_001085.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91

Genes affected

SERPINA3 (HGNC:16): (serpin family A member 3) 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. Polymorphisms in this protein appear to be tissue specific and influence protease targeting. Variations in this protein's sequence have been implicated in Alzheimer's disease, and deficiency of this protein has been associated with liver disease. Mutations have been identified in patients with Parkinson disease and chronic obstructive pulmonary disease. [provided by RefSeq, Jun 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA3	NM_001085.5	c.152C>A	p.Ser51Tyr	missense_variant	2/5	ENST00000393078.5
SERPINA3	NM_001384672.1	c.152C>A	p.Ser51Tyr	missense_variant	2/5
SERPINA3	NM_001384673.1	c.152C>A	p.Ser51Tyr	missense_variant	3/6
SERPINA3	NM_001384674.1	c.152C>A	p.Ser51Tyr	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA3	ENST00000393078.5	c.152C>A	p.Ser51Tyr	missense_variant	2/5	1	NM_001085.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2022

The c.152C>A (p.S51Y) alteration is located in exon 2 (coding exon 1) of the SERPINA3 gene. This alteration results from a C to A substitution at nucleotide position 152, causing the serine (S) at amino acid position 51 to be replaced by a tyrosine (Y). 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	0.11
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D;.;D
Eigen	Benign	-0.024
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.82	T;.;T;.
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.7	M;M;.;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.0	D;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.38
MutPred		0.53		Gain of catalytic residue at S51 (P = 5e-04);Gain of catalytic residue at S51 (P = 5e-04);Gain of catalytic residue at S51 (P = 5e-04);Gain of catalytic residue at S51 (P = 5e-04);
MVP		0.89
MPC		0.070
ClinPred		0.93	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.68
gMVP		0.27

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: chr14-95080930;