rs9630

chr14-94378638-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000295.5(SERPINA1):c.1068C>T(p.Ala356=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,613,330 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00088 (16 hom.)
• Consequence: SERPINA1 NM_000295.5 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.73

Genes affected

SERPINA1 (HGNC:8941): (serpin family A member 1) The protein encoded by this gene is a serine protease inhibitor belonging to the serpin superfamily whose targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator. This protein is produced in the liver, the bone marrow, by lymphocytic and monocytic cells in lymphoid tissue, and by the Paneth cells of the gut. Defects in this gene are associated with chronic obstructive pulmonary disease, emphysema, and chronic liver disease. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 14-94378638-G-A is Benign according to our data. Variant chr14-94378638-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-94378638-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00822 (1245/151520) while in subpopulation AFR AF= 0.0288 (1192/41360). AF 95% confidence interval is 0.0275. There are 12 homozygotes in gnomad4. There are 565 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.1068C>T	p.Ala356=	splice_region_variant, synonymous_variant	5/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.1068C>T	p.Ala356=	splice_region_variant, synonymous_variant	5/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes AF: 0.00817 AC: 1237 AN: 151402 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00257

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: 0.0000590

Gnomad OTH AF: 0.00480

GnomAD3 exomes AF: 0.00217 AC: 544 AN: 251030 Hom.: 3 AF XY: 0.00165 AC XY: 224 AN XY: 135694

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000880 AC: 1286 AN: 1461810 Hom.: 16 Cov.: 33 AF XY: 0.000752 AC XY: 547 AN XY: 727202

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000728

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00822 AC: 1245 AN: 151520 Hom.: 12 Cov.: 33 AF XY: 0.00764 AC XY: 565 AN XY: 73998

Gnomad4 AFR AF: 0.0288

Gnomad4 AMR AF: 0.00257

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000590

Gnomad4 OTH AF: 0.00475

Alfa AF: 0.0157 Hom.: 5

Bravo AF: 0.00927

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala356Ala in exon 7 of SERPINA1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 2.8% (122/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs9630). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Alpha-1-antitrypsin deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	2.9
Dann	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs9630; hg19: chr14-94844975;