rs17473

Positions:

• chr14-94619305-C-G
• chr14-94619305-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001085.5(SERPINA3):​c.754C>G​(p.Pro252Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,614,150 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (18 hom.)
• Consequence: SERPINA3 NM_001085.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: 0.0920

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 Benign. Variant got -12 ACMG points.

• BP6: Variant 14-94619305-C-G is Benign according to our data. Variant chr14-94619305-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 18050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-94619305-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA3	NM_001085.5	c.754C>G	p.Pro252Ala	missense_variant	3/5	ENST00000393078.5
SERPINA3	NM_001384672.1	c.754C>G	p.Pro252Ala	missense_variant	3/5
SERPINA3	NM_001384673.1	c.754C>G	p.Pro252Ala	missense_variant	4/6
SERPINA3	NM_001384674.1	c.754C>G	p.Pro252Ala	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA3	ENST00000393078.5	c.754C>G	p.Pro252Ala	missense_variant	3/5	1	NM_001085.5	P1

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 468 AN: 152140 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00576

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00286 AC: 718 AN: 251450 Hom.: 3 AF XY: 0.00282 AC XY: 383 AN XY: 135908

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00572

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00472 AC: 6894 AN: 1461892 Hom.: 18 Cov.: 32 AF XY: 0.00451 AC XY: 3278 AN XY: 727248

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000805

Gnomad4 NFE exome AF: 0.00592

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.00307 AC: 468 AN: 152258 Hom.: 2 Cov.: 32 AF XY: 0.00289 AC XY: 215 AN XY: 74446

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00576

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00518 Hom.: 2

Bravo AF: 0.00298

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00302 AC: 367

EpiCase AF: 0.00431

EpiControl AF: 0.00415

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	SERPINA3: PP3, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2022	See Variant Classification Assertion Criteria. -

ANTICHYMOTRYPSIN BONN 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 04, 1993

- -

SERPINA3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Benign	0.82
DEOGEN2	Uncertain	0.54	D;D;.;D;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.82	T;.;T;.;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.5	L;L;.;L;.
MutationTaster	Benign	1.8e-8	A;A;A;A;A
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-5.6	D;D;D;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.099	T;T;T;T;T
Sift4G	Benign	0.48	T;T;T;T;T
Polyphen		0.027	B;B;.;B;.
Vest4		0.18
MVP		0.90
MPC		0.036
ClinPred		0.013	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.67		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17473; hg19: chr14-95085642;