chr14-94382864-C-T

Variant names:

• chr14-94382864-C-T
• rs709932
• NM_000295.5:c.374G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000295.5(SERPINA1):​c.374G>A​(p.Arg125His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,614,092 control chromosomes in the GnomAD database, including 21,879 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1593 hom., cov: 33)
  • Exomes 𝑓: 0.16 (20286 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:2
• Conservation: PhyloP100: -0.566
• Publications: 75 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047332942).
• BP6: Variant 14-94382864-C-T is Benign according to our data. Variant chr14-94382864-C-T is described in ClinVar as Benign. ClinVar VariationId is 17957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.267 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.374G>A	p.Arg125His	missense	Exon 2 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.374G>A	p.Arg125His	missense	Exon 2 of 5	NP_001002235.1	E9KL23
	SERPINA1	NM_001002236.3		c.374G>A	p.Arg125His	missense	Exon 4 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.374G>A	p.Arg125His	missense	Exon 2 of 5	ENSP00000376802.4	P01009-1
	SERPINA1	ENST00000355814.8	TSL:1	c.374G>A	p.Arg125His	missense	Exon 2 of 5	ENSP00000348068.4	P01009-1
	SERPINA1	ENST00000393088.8	TSL:1	c.374G>A	p.Arg125His	missense	Exon 4 of 7	ENSP00000376803.4	P01009-1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19194 AN: 152102 Hom.: 1583 Cov.: 33

Gnomad AFR AF: 0.0391

Gnomad AMI AF: 0.0936

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.140

GnomAD2 exomes AF: 0.160 AC: 40211 AN: 251352 AF XY: 0.171

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.207

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.161 AC: 235568 AN: 1461870 Hom.: 20286 Cov.: 33 AF XY: 0.166 AC XY: 120413 AN XY: 727230

African (AFR) AF: 0.0317 AC: 1061 AN: 33480

American (AMR) AF: 0.110 AC: 4911 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 4154 AN: 26134

East Asian (EAS) AF: 0.228 AC: 9039 AN: 39698

South Asian (SAS) AF: 0.268 AC: 23084 AN: 86258

European-Finnish (FIN) AF: 0.126 AC: 6747 AN: 53420

Middle Eastern (MID) AF: 0.189 AC: 1089 AN: 5768

European-Non Finnish (NFE) AF: 0.158 AC: 175480 AN: 1111992

Other (OTH) AF: 0.166 AC: 10003 AN: 60396

GnomAD4 genome AF: 0.126 AC: 19215 AN: 152222 Hom.: 1593 Cov.: 33 AF XY: 0.128 AC XY: 9500 AN XY: 74426

African (AFR) AF: 0.0393 AC: 1632 AN: 41532

American (AMR) AF: 0.121 AC: 1848 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 561 AN: 3468

East Asian (EAS) AF: 0.221 AC: 1142 AN: 5178

South Asian (SAS) AF: 0.280 AC: 1349 AN: 4826

European-Finnish (FIN) AF: 0.121 AC: 1284 AN: 10592

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10937 AN: 68012

Other (OTH) AF: 0.147 AC: 310 AN: 2112

Alfa AF: 0.153 Hom.: 6733

Bravo AF: 0.117

TwinsUK AF: 0.160 AC: 593

ALSPAC AF: 0.150 AC: 578

ESP6500AA AF: 0.0363 AC: 160

ESP6500EA AF: 0.165 AC: 1421

ExAC AF: 0.163 AC: 19806

Asia WGS AF: 0.237 AC: 825 AN: 3478

EpiCase AF: 0.169

EpiControl AF: 0.172

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Alpha-1-antitrypsin deficiency (5)
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	-	PI M2 (1)
-	-	-	PI M4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.17
DANN	Benign	0.60
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.57
PrimateAI	Benign	0.18	T
PROVEAN	Benign	3.1	N
REVEL	Benign	0.24
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0070
MPC		0.051
ClinPred		0.0016	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.075
gMVP		0.27
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: rs709932; hg19: chr14-94849201; COSMIC: COSV63345368; COSMIC: COSV63345368;