rs121912725

Variant names:

• chr11-116837035-G-A
• rs121912725
• NM_000039.3:c.166C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000039.3(APOA1):​c.166C>T​(p.Gln56*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Q56Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: APOA1 NM_000039.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.55
• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 24 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-116837035-G-A is Pathogenic according to our data. Variant chr11-116837035-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17926.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOA1	NM_000039.3	MANE Select	c.166C>T	p.Gln56*	stop_gained	Exon 3 of 4	NP_000030.1
	APOA1	NM_001318017.2		c.166C>T	p.Gln56*	stop_gained	Exon 3 of 4	NP_001304946.1
	APOA1	NM_001318018.2		c.166C>T	p.Gln56*	stop_gained	Exon 3 of 4	NP_001304947.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOA1	ENST00000236850.5	TSL:1 MANE Select	c.166C>T	p.Gln56*	stop_gained	Exon 3 of 4	ENSP00000236850.3
	APOA1	ENST00000375323.5	TSL:1	c.166C>T	p.Gln56*	stop_gained	Exon 2 of 3	ENSP00000364472.1
	APOA1	ENST00000359492.6	TSL:2	c.166C>T	p.Gln56*	stop_gained	Exon 3 of 4	ENSP00000352471.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hypoalphalipoproteinemia, primary, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		3.6
Vest4		0.96
GERP RS		3.9
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121912725; hg19: chr11-116707751;