14-94378506-T-G

Variant names:

• chr14-94378506-T-G
• rs1303
• NM_000295.5:c.1200A>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000295.5(SERPINA1):​c.1200A>C​(p.Glu400Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,613,760 control chromosomes in the GnomAD database, including 57,937 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4621 hom., cov: 32)
  • Exomes 𝑓: 0.26 (53316 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -2.75
• Publications: 95 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 -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000295.5
• BP4: Computational evidence support a benign effect (MetaRNN=4.7135353E-4).
• BP6: Variant 14-94378506-T-G is Benign according to our data. Variant chr14-94378506-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 17958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

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.1200A>C	p.Glu400Asp	missense	Exon 5 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.1200A>C	p.Glu400Asp	missense	Exon 5 of 5	NP_001002235.1	E9KL23
	SERPINA1	NM_001002236.3		c.1200A>C	p.Glu400Asp	missense	Exon 7 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.1200A>C	p.Glu400Asp	missense	Exon 5 of 5	ENSP00000376802.4	P01009-1
	SERPINA1	ENST00000355814.8	TSL:1	c.1200A>C	p.Glu400Asp	missense	Exon 5 of 5	ENSP00000348068.4	P01009-1
	SERPINA1	ENST00000393088.8	TSL:1	c.1200A>C	p.Glu400Asp	missense	Exon 7 of 7	ENSP00000376803.4	P01009-1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34671 AN: 151882 Hom.: 4601 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.240

GnomAD2 exomes AF: 0.277 AC: 69749 AN: 251452 AF XY: 0.287

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.322

Gnomad ASJ exome AF: 0.266

Gnomad EAS exome AF: 0.284

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.275

GnomAD4 exome AF: 0.265 AC: 387193 AN: 1461760 Hom.: 53316 Cov.: 36 AF XY: 0.270 AC XY: 196696 AN XY: 727200

African (AFR) AF: 0.103 AC: 3452 AN: 33480

American (AMR) AF: 0.326 AC: 14575 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 6918 AN: 26130

East Asian (EAS) AF: 0.286 AC: 11373 AN: 39698

South Asian (SAS) AF: 0.421 AC: 36278 AN: 86258

European-Finnish (FIN) AF: 0.241 AC: 12899 AN: 53418

Middle Eastern (MID) AF: 0.312 AC: 1798 AN: 5768

European-Non Finnish (NFE) AF: 0.255 AC: 283733 AN: 1111894

Other (OTH) AF: 0.268 AC: 16167 AN: 60394

GnomAD4 genome AF: 0.228 AC: 34717 AN: 152000 Hom.: 4621 Cov.: 32 AF XY: 0.235 AC XY: 17427 AN XY: 74268

African (AFR) AF: 0.112 AC: 4667 AN: 41494

American (AMR) AF: 0.333 AC: 5094 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 931 AN: 3472

East Asian (EAS) AF: 0.298 AC: 1530 AN: 5130

South Asian (SAS) AF: 0.433 AC: 2083 AN: 4810

European-Finnish (FIN) AF: 0.235 AC: 2487 AN: 10570

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.253 AC: 17191 AN: 67934

Other (OTH) AF: 0.245 AC: 517 AN: 2108

Alfa AF: 0.245 Hom.: 19518

Bravo AF: 0.223

TwinsUK AF: 0.251 AC: 931

ALSPAC AF: 0.250 AC: 963

ESP6500AA AF: 0.107 AC: 472

ESP6500EA AF: 0.258 AC: 2222

ExAC AF: 0.275 AC: 33350

Asia WGS AF: 0.336 AC: 1169 AN: 3478

EpiCase AF: 0.259

EpiControl AF: 0.263

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Alpha-1-antitrypsin deficiency (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	-	PI M3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.0010
DANN	Benign	0.11
DEOGEN2	Benign	0.12	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.00047	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.58	N
PhyloP100		-2.8
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.036
MutPred		0.35		Gain of catalytic residue at Q401 (P = 9e-04)
MPC		0.042
ClinPred		0.015	T
GERP RS		-9.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.37
Mutation Taster		=100/0	polymorphism (auto)

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: rs1303; hg19: chr14-94844843; COSMIC: COSV63345434; COSMIC: COSV63345434;