rs11846959

Variant names:

• chr14-94379979-G-A
• rs11846959
• NM_000295.5:c.918-368C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-94379979-G-A
• chr14-94379979-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000393087.9(SERPINA1):​c.918-368C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 142,100 control chromosomes in the GnomAD database, including 3,518 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (3518 hom., cov: 34)
• Consequence: SERPINA1 ENST00000393087.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• Publications: 11 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, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000393087.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	NM_000295.5	MANE Select	c.918-368C>T		intron	N/A	NP_000286.3
	SERPINA1	NM_001002235.3		c.918-368C>T		intron	N/A	NP_001002235.1
	SERPINA1	NM_001002236.3		c.918-368C>T		intron	N/A	NP_001002236.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	ENST00000393087.9	TSL:1 MANE Select	c.918-368C>T		intron	N/A	ENSP00000376802.4
	SERPINA1	ENST00000355814.8	TSL:1	c.918-368C>T		intron	N/A	ENSP00000348068.4
	SERPINA1	ENST00000393088.8	TSL:1	c.918-368C>T		intron	N/A	ENSP00000376803.4

Frequencies

GnomAD3 genomes AF: 0.248 AC: 35153 AN: 141992 Hom.: 3505 Cov.: 34

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.257

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.248 AC: 35198 AN: 142100 Hom.: 3518 Cov.: 34 AF XY: 0.253 AC XY: 17489 AN XY: 69020

African (AFR) AF: 0.180 AC: 7113 AN: 39410

American (AMR) AF: 0.335 AC: 4705 AN: 14054

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 869 AN: 3256

East Asian (EAS) AF: 0.297 AC: 1353 AN: 4554

South Asian (SAS) AF: 0.416 AC: 1845 AN: 4430

European-Finnish (FIN) AF: 0.242 AC: 2339 AN: 9666

Middle Eastern (MID) AF: 0.314 AC: 86 AN: 274

European-Non Finnish (NFE) AF: 0.255 AC: 16248 AN: 63630

Other (OTH) AF: 0.262 AC: 523 AN: 2000

Alfa AF: 0.251 Hom.: 12162

Asia WGS AF: 0.343 AC: 1194 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.44
PhyloP100		-1.5
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: rs11846959; hg19: chr14-94846316;