14-94612340-G-T

Position:

• chr14-94612340-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The 14-94612340-G-T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 1,210,174 control chromosomes in the GnomAD database, including 150,989 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (16535 hom., cov: 32)
  • Exomes 𝑓: 0.50 (134454 hom.)
• Consequence: SERPINA3 ENST00000393080.8 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.175

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA3	ENST00000393080.8			upstream_gene_variant		1		P1
SERPINA3	ENST00000485588.1			upstream_gene_variant		1
SERPINA3	ENST00000555820.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69145 AN: 151824 Hom.: 16526 Cov.: 32

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.602

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.463

GnomAD3 exomes AF: 0.478 AC: 104561 AN: 218662 Hom.: 26204 AF XY: 0.487 AC XY: 57890 AN XY: 118974

Gnomad AFR exome AF: 0.339

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.648

Gnomad SAS exome AF: 0.460

Gnomad FIN exome AF: 0.602

Gnomad NFE exome AF: 0.511

Gnomad OTH exome AF: 0.487

GnomAD4 exome AF: 0.500 AC: 528739 AN: 1058230 Hom.: 134454 Cov.: 14 AF XY: 0.500 AC XY: 264997 AN XY: 530010

Gnomad4 AFR exome AF: 0.327

Gnomad4 AMR exome AF: 0.262

Gnomad4 ASJ exome AF: 0.561

Gnomad4 EAS exome AF: 0.645

Gnomad4 SAS exome AF: 0.462

Gnomad4 FIN exome AF: 0.600

Gnomad4 NFE exome AF: 0.511

Gnomad4 OTH exome AF: 0.499

GnomAD4 genome AF: 0.455 AC: 69172 AN: 151944 Hom.: 16535 Cov.: 32 AF XY: 0.460 AC XY: 34120 AN XY: 74254

Gnomad4 AFR AF: 0.337

Gnomad4 AMR AF: 0.347

Gnomad4 ASJ AF: 0.554

Gnomad4 EAS AF: 0.635

Gnomad4 SAS AF: 0.455

Gnomad4 FIN AF: 0.602

Gnomad4 NFE AF: 0.511

Gnomad4 OTH AF: 0.468

Alfa AF: 0.495 Hom.: 39756

Bravo AF: 0.433

Asia WGS AF: 0.510 AC: 1777 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.8
DANN	Benign	0.87

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1884082; hg19: chr14-95078677; COSMIC: COSV67585272;