NM_000039.3:c.220T>C

Variant names:

• chr11-116836392-A-G
• rs121912726
• NM_000039.3:c.220T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM2 PP3_Strong PP5_Moderate

The NM_000039.3(APOA1):​c.220T>C​(p.Trp74Arg) variant causes a missense 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 (★). ClinVar reports functional evidence for this variant: "SCV004294952: Experimental studies have shown that this missense change affects APOA1 function (PMID:21296086, 24702826).".

• Frequency: Genomes: not found (cov: 33)
• Consequence: APOA1 NM_000039.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.22
• Publications: 4 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 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004294952: Experimental studies have shown that this missense change affects APOA1 function (PMID: 21296086, 24702826).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 11-116836392-A-G is Pathogenic according to our data. Variant chr11-116836392-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 17928.Status of the report is criteria_provided_single_submitter, 1 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.220T>C	p.Trp74Arg	missense	Exon 4 of 4	NP_000030.1	A0A024R3E3
	APOA1	NM_001318017.2		c.220T>C	p.Trp74Arg	missense	Exon 4 of 4	NP_001304946.1	A0A024R3E3
	APOA1	NM_001318018.2		c.220T>C	p.Trp74Arg	missense	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.220T>C	p.Trp74Arg	missense	Exon 4 of 4	ENSP00000236850.3	P02647
	APOA1	ENST00000375323.5	TSL:1	c.220T>C	p.Trp74Arg	missense	Exon 3 of 3	ENSP00000364472.1	P02647
	APOA1	ENST00000855312.1		c.253T>C	p.Trp85Arg	missense	Exon 4 of 4	ENSP00000525371.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Familial amyloid polyneuropathy, Iowa type (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.2
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.97	D
Vest4		0.78
MutPred		0.78		Gain of disorder (P = 0.0019)
MVP		0.88
MPC		2.1
ClinPred		0.97	D
GERP RS		2.6
Varity_R		0.93
gMVP		0.66
Mutation Taster		=0/100	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: rs121912726; hg19: chr11-116707108;