chr14-94614436-T-C

Variant names:

• chr14-94614436-T-C
• rs144870571
• NM_001085.5:c.-6T>C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001085.5(SERPINA3):​c.-6T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,613,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SERPINA3 NM_001085.5 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.00002784
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.511

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

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 14-94614436-T-C is Benign according to our data. Variant chr14-94614436-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3039814.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA3	NM_001085.5	c.-6T>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 5	ENST00000393078.5	NP_001076.2
SERPINA3	NM_001085.5	c.-6T>C		splice_region_variant	Exon 2 of 5	ENST00000393078.5	NP_001076.2
SERPINA3	NM_001085.5	c.-6T>C		5_prime_UTR_variant	Exon 2 of 5	ENST00000393078.5	NP_001076.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA3	ENST00000393078	c.-6T>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 5	1	NM_001085.5	ENSP00000376793.3
SERPINA3	ENST00000393078.5	c.-6T>C		splice_region_variant	Exon 2 of 5	1	NM_001085.5	ENSP00000376793.3
SERPINA3	ENST00000393078	c.-6T>C		5_prime_UTR_variant	Exon 2 of 5	1	NM_001085.5	ENSP00000376793.3
ENSG00000273259	ENST00000553947.1	n.*821T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 8	2		ENSP00000452367.2
ENSG00000273259	ENST00000553947.1	n.*821T>C		3_prime_UTR_variant	Exon 5 of 8	2		ENSP00000452367.2

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 151976 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000284 AC: 71 AN: 249840 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135090

Gnomad AFR exome AF: 0.00415

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000120 AC: 176 AN: 1461032 Hom.: 0 Cov.: 29 AF XY: 0.000110 AC XY: 80 AN XY: 726834

Gnomad4 AFR exome AF: 0.00457

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.00130 AC: 197 AN: 152090 Hom.: 1 Cov.: 31 AF XY: 0.00117 AC XY: 87 AN XY: 74324

Gnomad4 AFR AF: 0.00458

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000331 Hom.: 0

Bravo AF: 0.00133

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

SERPINA3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2019

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
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.39
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
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

LitVar

Other links and lift over

dbSNP: rs144870571; hg19: chr14-95080773;