Genetic Variant NM_000039.3:c.43+41T>C (chr11-116837304-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000039.3(APOA1):c.43+41T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 1,583,486 control chromosomes in the GnomAD database, including 332,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.59 ( 27300 hom., cov: 32)

Exomes 𝑓: 0.64 ( 305512 hom. )

Consequence

APOA1
NM_000039.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.67

Publications

32 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 links:

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

APOA1-AS links:

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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=-0.84).

BP6

Variant 11-116837304-A-G is Benign according to our data. Variant chr11-116837304-A-G is described in ClinVar as Benign. ClinVar VariationId is 1225953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

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.43+41T>C	intron	N/A	NP_000030.1	A0A024R3E3
APOA1	NM_001318017.2		c.43+41T>C	intron	N/A	NP_001304946.1	A0A024R3E3
APOA1	NM_001318018.2		c.43+41T>C	intron	N/A	NP_001304947.1	P02647

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APOA1	ENST00000236850.5	TSL:1 MANE Select	c.43+41T>C	intron	N/A	ENSP00000236850.3	P02647
APOA1	ENST00000375323.5	TSL:1	c.43+41T>C	intron	N/A	ENSP00000364472.1	P02647
APOA1	ENST00000855312.1		c.43+41T>C	intron	N/A	ENSP00000525371.1

Frequencies

GnomAD3 genomes

AF:

0.590

AC:

89601

AN:

151904

Hom.:

27297

Cov.:

show subpopulations

Gnomad AFR

AF:

0.522

Gnomad AMI

AF:

0.822

Gnomad AMR

AF:

0.536

Gnomad ASJ

AF:

0.615

Gnomad EAS

AF:

0.269

Gnomad SAS

AF:

0.369

Gnomad FIN

AF:

0.565

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.683

Gnomad OTH

AF:

0.583

GnomAD2 exomes

AF:

0.557

AC:

112149

AN:

201366

AF XY:

0.557

show subpopulations

Gnomad AFR exome

AF:

0.514

Gnomad AMR exome

AF:

0.458

Gnomad ASJ exome

AF:

0.624

Gnomad EAS exome

AF:

0.268

Gnomad FIN exome

AF:

0.571

Gnomad NFE exome

AF:

0.686

Gnomad OTH exome

AF:

0.599

GnomAD4 exome

AF:

0.643

AC:

920676

AN:

1431466

Hom.:

305512

Cov.:

AF XY:

0.636

AC XY:

450989

AN XY:

709512

show subpopulations

African (AFR)

AF:

0.511

AC:

16874

AN:

33052

American (AMR)

AF:

0.468

AC:

18189

AN:

38844

Ashkenazi Jewish (ASJ)

AF:

0.619

AC:

15800

AN:

25522

East Asian (EAS)

AF:

0.236

AC:

9137

AN:

38698

South Asian (SAS)

AF:

0.386

AC:

32138

AN:

83358

European-Finnish (FIN)

AF:

0.573

AC:

29327

AN:

51222

Middle Eastern (MID)

AF:

0.530

AC:

3034

AN:

5720

European-Non Finnish (NFE)

AF:

0.694

AC:

760017

AN:

1095718

Other (OTH)

AF:

0.609

AC:

36160

AN:

59332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

18771

37543

56314

75086

93857

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19188

38376

57564

76752

95940

<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:

0.590

AC:

89624

AN:

152020

Hom.:

27300

Cov.:

AF XY:

0.579

AC XY:

43037

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.522

AC:

21641

AN:

41464

American (AMR)

AF:

0.535

AC:

8179

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.615

AC:

2133

AN:

3466

East Asian (EAS)

AF:

0.269

AC:

1389

AN:

5162

South Asian (SAS)

AF:

0.369

AC:

1777

AN:

4812

European-Finnish (FIN)

AF:

0.565

AC:

5971

AN:

10568

Middle Eastern (MID)

AF:

0.514

AC:

151

AN:

294

European-Non Finnish (NFE)

AF:

0.683

AC:

46420

AN:

67946

Other (OTH)

AF:

0.576

AC:

1217

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1840

3681

5521

7362

9202

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

742

1484

2226

2968

3710

<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:

0.619

Hom.:

5934

Bravo

AF:

0.587

Asia WGS

AF:

0.302

AC:

1052

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Familial visceral amyloidosis, Ostertag type (1)

Hypoalphalipoproteinemia, primary, 2 (1)

Hypoalphalipoproteinemia, primary, 2, intermediate (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.57

PhyloP100

1.7

PromoterAI

0.017

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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