rs116929575

Positions:

• chr14-94623782-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001085.5(SERPINA3):​c.1240A>G​(p.Met414Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000735 in 1,614,118 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (19 hom.)
• Consequence: SERPINA3 NM_001085.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: -2.54

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0952588).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000771 (1127/1461882) while in subpopulation EAS AF= 0.027 (1070/39700). AF 95% confidence interval is 0.0256. There are 19 homozygotes in gnomad4_exome. There are 541 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA3	NM_001085.5	c.1240A>G	p.Met414Val	missense_variant	5/5	ENST00000393078.5
SERPINA3	NM_001384672.1	c.1240A>G	p.Met414Val	missense_variant	5/5
SERPINA3	NM_001384673.1	c.1240A>G	p.Met414Val	missense_variant	6/6
SERPINA3	NM_001384674.1	c.1240A>G	p.Met414Val	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA3	ENST00000393078.5	c.1240A>G	p.Met414Val	missense_variant	5/5	1	NM_001085.5	P1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152118 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0103

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000855 AC: 215 AN: 251458 Hom.: 3 AF XY: 0.000773 AC XY: 105 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0113

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000771 AC: 1127 AN: 1461882 Hom.: 19 Cov.: 31 AF XY: 0.000744 AC XY: 541 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0270

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152236 Hom.: 1 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74426

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0101

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000942 Hom.: 2

Bravo AF: 0.000389

ExAC AF: 0.000881 AC: 107

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

ANTICHYMOTRYPSIN ISEHARA 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2001

- -

Peripheral arterial occlusive disease 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	0.073
DANN	Benign	0.36
DEOGEN2	Benign	0.25	T;T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.18	T;.;.;T
MetaRNN	Benign	0.095	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.72	N;N;N;.
MutationTaster	Benign	1.6e-7	A;A;A;A;A
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.65
MVP		0.16
MPC		0.011
ClinPred		0.027	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs116929575; hg19: chr14-95090119;