rs121912716

Variant names:

• chr11-116836221-T-A
• rs121912716
• NM_000039.3:c.391A>T

Your query was ambiguous. Multiple possible variants found:

• chr11-116836221-T-A
• chr11-116836221-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_000039.3(APOA1):​c.391A>T​(p.Lys131*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: APOA1 NM_000039.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.35
• Publications: 1 publications found

Genes affected

APOA1 (HGNC:600): (apolipoprotein A1) This gene encodes apolipoprotein A-I, which is the major protein component of high density lipoprotein (HDL) in plasma. The encoded preproprotein is proteolytically processed to generate the mature protein, which promotes cholesterol efflux from tissues to the liver for excretion, and is a cofactor for lecithin cholesterolacyltransferase (LCAT), an enzyme responsible for the formation of most plasma cholesteryl esters. This gene is closely linked with two other apolipoprotein genes on chromosome 11. Defects in this gene are associated with HDL deficiencies, including Tangier disease, and with systemic non-neuropathic amyloidosis. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein. [provided by RefSeq, Dec 2015]

APOA1-AS (HGNC:40079): (APOA1 antisense RNA)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-116836221-T-A is Pathogenic according to our data. Variant chr11-116836221-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17911.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000039.3. 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
	APOA1	NM_000039.3	MANE Select	c.391A>T	p.Lys131*	stop_gained	Exon 4 of 4	NP_000030.1	A0A024R3E3
	APOA1	NM_001318017.2		c.391A>T	p.Lys131*	stop_gained	Exon 4 of 4	NP_001304946.1	A0A024R3E3
	APOA1	NM_001318018.2		c.391A>T	p.Lys131*	stop_gained	Exon 4 of 4	NP_001304947.1	P02647

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOA1	ENST00000236850.5	TSL:1 MANE Select	c.391A>T	p.Lys131*	stop_gained	Exon 4 of 4	ENSP00000236850.3	P02647
	APOA1	ENST00000375323.5	TSL:1	c.391A>T	p.Lys131*	stop_gained	Exon 3 of 3	ENSP00000364472.1	P02647
	APOA1	ENST00000855312.1		c.424A>T	p.Lys142*	stop_gained	Exon 4 of 4	ENSP00000525371.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460928 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726814

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111254

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	APOLIPOPROTEIN A-I (MARBURG) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.51	D
PhyloP100		1.3
Vest4		0.88
GERP RS		5.3
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs121912716; hg19: chr11-116706937;