14-94619305-C-A

Variant names:

• chr14-94619305-C-A
• rs17473
• NM_001085.5:c.754C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001085.5(SERPINA3):​c.754C>A​(p.Pro252Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P252A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SERPINA3 NM_001085.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0920
• Publications: 0 publications found

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]

ENSG00000273259 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001085.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA3	NM_001085.5	MANE Select	c.754C>A	p.Pro252Thr	missense	Exon 3 of 5	NP_001076.2	P01011-1
	SERPINA3	NM_001384672.1		c.754C>A	p.Pro252Thr	missense	Exon 3 of 5	NP_001371601.1	P01011-1
	SERPINA3	NM_001384673.1		c.754C>A	p.Pro252Thr	missense	Exon 4 of 6	NP_001371602.1	P01011-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA3	ENST00000393078.5	TSL:1 MANE Select	c.754C>A	p.Pro252Thr	missense	Exon 3 of 5	ENSP00000376793.3	P01011-1
	SERPINA3	ENST00000393080.8	TSL:1	c.754C>A	p.Pro252Thr	missense	Exon 3 of 5	ENSP00000376795.4	P01011-1
	SERPINA3	ENST00000482740.2	TSL:1	c.100C>A	p.Pro34Thr	missense	Exon 1 of 3	ENSP00000451119.1	G3V3A0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.086
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.092
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.33
Sift	Benign	0.058	T
Sift4G	Benign	0.24	T
Polyphen		0.88	P
Vest4		0.33
MutPred		0.49		Gain of catalytic residue at F254 (P = 0.0017)
MVP		0.90
MPC		0.071
ClinPred		0.68	D
GERP RS		3.8
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.61
gMVP		0.42
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs17473; hg19: chr14-95085642;