rs141620200

Variant names:

• chr14-94379607-C-A
• rs141620200
• NM_000295.5:c.922G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-94379607-C-A
• chr14-94379607-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000295.5(SERPINA1):​c.922G>T​(p.Ala308Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,613,904 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A308T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0033 (11 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: -0.142
• Publications: 23 publications found

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]

SERPINA1 Gene-Disease associations (from GenCC):

• alpha 1-antitrypsin deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059836507).
• BP6: Variant 14-94379607-C-A is Benign according to our data. Variant chr14-94379607-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288456.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00212 (322/152034) while in subpopulation NFE AF = 0.00399 (271/67956). AF 95% confidence interval is 0.0036. There are 3 homozygotes in GnomAd4. There are 159 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000295.5. 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
	SERPINA1	NM_000295.5	MANE Select	c.922G>T	p.Ala308Ser	missense	Exon 4 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.922G>T	p.Ala308Ser	missense	Exon 4 of 5	NP_001002235.1	E9KL23
	SERPINA1	NM_001002236.3		c.922G>T	p.Ala308Ser	missense	Exon 6 of 7	NP_001002236.1	E9KL23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	ENST00000393087.9	TSL:1 MANE Select	c.922G>T	p.Ala308Ser	missense	Exon 4 of 5	ENSP00000376802.4	P01009-1
	SERPINA1	ENST00000355814.8	TSL:1	c.922G>T	p.Ala308Ser	missense	Exon 4 of 5	ENSP00000348068.4	P01009-1
	SERPINA1	ENST00000393088.8	TSL:1	c.922G>T	p.Ala308Ser	missense	Exon 6 of 7	ENSP00000376803.4	P01009-1

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 322 AN: 151916 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00399

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00201 AC: 506 AN: 251208 AF XY: 0.00199

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00208

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00331 AC: 4840 AN: 1461870 Hom.: 11 Cov.: 31 AF XY: 0.00322 AC XY: 2343 AN XY: 727240

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000803 AC: 21 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: 0.00176 AC: 94 AN: 53402

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

European-Non Finnish (NFE) AF: 0.00410 AC: 4558 AN: 1112008

Other (OTH) AF: 0.00242 AC: 146 AN: 60394

GnomAD4 genome AF: 0.00212 AC: 322 AN: 152034 Hom.: 3 Cov.: 34 AF XY: 0.00214 AC XY: 159 AN XY: 74356

African (AFR) AF: 0.000723 AC: 30 AN: 41484

American (AMR) AF: 0.000197 AC: 3 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00399 AC: 271 AN: 67956

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00288 Hom.: 6

Bravo AF: 0.00173

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00234 AC: 284

EpiCase AF: 0.00273

EpiControl AF: 0.00261

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Alpha-1-antitrypsin deficiency (2)
-	1	1	not provided (2)
-	-	2	not specified (2)
-	1	-	SERPINA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.14
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.27
Sift	Benign	0.065	T
Sift4G	Benign	0.40	T
Polyphen		0.0030	B
Vest4		0.44
MVP		0.99
MPC		0.059
ClinPred		0.014	T
GERP RS		3.4
Varity_R		0.47
gMVP		0.46
Mutation Taster		=99/1	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: rs141620200; hg19: chr14-94845944;