11-116835831-T-A

Variant names:

• chr11-116835831-T-A
• rs143430381
• NM_000039.3:c.781A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000039.3(APOA1):​c.781A>T​(p.Thr261Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T261A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APOA1 NM_000039.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -7.38
• Publications: 2 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 Gene-Disease associations (from GenCC):

• familial visceral amyloidosis

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypoalphalipoproteinemia, primary, 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• AApoAI amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• apolipoprotein A-I deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029905558).

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.781A>T	p.Thr261Ser	missense	Exon 4 of 4	NP_000030.1	A0A024R3E3
	APOA1	NM_001318017.2		c.781A>T	p.Thr261Ser	missense	Exon 4 of 4	NP_001304946.1	A0A024R3E3
	APOA1	NM_001318018.2		c.781A>T	p.Thr261Ser	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.781A>T	p.Thr261Ser	missense	Exon 4 of 4	ENSP00000236850.3	P02647
	APOA1	ENST00000375323.5	TSL:1	c.781A>T	p.Thr261Ser	missense	Exon 3 of 3	ENSP00000364472.1	P02647
	APOA1	ENST00000855312.1		c.814A>T	p.Thr272Ser	missense	Exon 4 of 4	ENSP00000525371.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 247842 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460758 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726692

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0010
DANN	Benign	0.80
DEOGEN2	Benign	0.088	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.39	N
PhyloP100		-7.4
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.084
Sift	Benign	1.0	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.088
MutPred		0.28		Gain of disorder (P = 0.0287)
MVP		0.69
MPC		0.54
ClinPred		0.066	T
GERP RS		-9.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.12
Mutation Taster		=90/10	polymorphism

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: rs143430381; hg19: chr11-116706547;