Genetic Variant APOA1:c.*19C>G (chr11-116835789-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000039.3(APOA1):c.*19C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000386 in 1,613,034 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00039 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00039 ( 4 hom. )

Consequence

APOA1
NM_000039.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0340

Publications

1 publications found

Variant links:

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

APOA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 11-116835789-G-C is Benign according to our data. Variant chr11-116835789-G-C is described in ClinVar as Benign. ClinVar VariationId is 302500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000387 (59/152384) while in subpopulation SAS AF = 0.00435 (21/4828). AF 95% confidence interval is 0.00291. There are 1 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APOA1	NM_000039.3	MANE Select	c.*19C>G	3_prime_UTR	Exon 4 of 4	NP_000030.1	A0A024R3E3
APOA1	NM_001318017.2		c.*19C>G	3_prime_UTR	Exon 4 of 4	NP_001304946.1	A0A024R3E3
APOA1	NM_001318018.2		c.*19C>G	3_prime_UTR	Exon 4 of 4	NP_001304947.1	P02647

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APOA1	ENST00000236850.5	TSL:1 MANE Select	c.*19C>G	3_prime_UTR	Exon 4 of 4	ENSP00000236850.3	P02647
APOA1	ENST00000375323.5	TSL:1	c.*19C>G	3_prime_UTR	Exon 3 of 3	ENSP00000364472.1	P02647
APOA1	ENST00000855312.1		c.*19C>G	3_prime_UTR	Exon 4 of 4	ENSP00000525371.1

Frequencies

GnomAD3 genomes

AF:

0.000387

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000648

AC:

159

AN:

245468

AF XY:

0.000774

show subpopulations

Gnomad AFR exome

AF:

0.000207

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000209

Gnomad OTH exome

AF:

0.000665

GnomAD4 exome

AF:

0.000385

AC:

563

AN:

1460650

Hom.:

Cov.:

AF XY:

0.000500

AC XY:

363

AN XY:

726642

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33478

American (AMR)

AF:

0.000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00368

AC:

317

AN:

86210

European-Finnish (FIN)

AF:

0.0000382

AC:

AN:

52308

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000133

AC:

148

AN:

1111962

Other (OTH)

AF:

0.000845

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

101

135

169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000387

AC:

AN:

152384

Hom.:

Cov.:

AF XY:

0.000523

AC XY:

AN XY:

74524

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41604

American (AMR)

AF:

0.000980

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00435

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68042

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000718

Hom.:

Bravo

AF:

0.000453

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial visceral amyloidosis, Ostertag type (2)

Hypoalphalipoproteinemia, primary, 1 (1)

Hypoalphalipoproteinemia, primary, 2 (1)

Hypoalphalipoproteinemia, primary, 2, intermediate (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

4.4

(source)

DANN

Benign

0.37

PhyloP100

-0.034

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over