11-116790254-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001371904.1(APOA5):c.975C>T(p.Ala325=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000626 in 1,614,254 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 0.0034 (3 hom., cov: 34)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: APOA5 NM_001371904.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.109

Genes affected

APOA5 (HGNC:17288): (apolipoprotein A5) The protein encoded by this gene is an apolipoprotein that plays an important role in regulating the plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of high density lipoprotein and is highly similar to a rat protein that is upregulated in response to liver injury. Mutations in this gene have been associated with hypertriglyceridemia and hyperlipoproteinemia type 5. This gene is located proximal to the apolipoprotein gene cluster on chromosome 11q23. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-116790254-G-A is Benign according to our data. Variant chr11-116790254-G-A is described in ClinVar as [Benign]. Clinvar id is 496501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-116790254-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.109 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00337 (513/152362) while in subpopulation AFR AF= 0.0118 (489/41580). AF 95% confidence interval is 0.0109. There are 3 homozygotes in gnomad4. There are 254 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOA5	NM_001371904.1	c.975C>T	p.Ala325=	synonymous_variant	3/3	ENST00000227665.9
APOA5	NM_001166598.2	c.975C>T	p.Ala325=	synonymous_variant	4/4
APOA5	NM_052968.5	c.975C>T	p.Ala325=	synonymous_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOA5	ENST00000227665.9	c.975C>T	p.Ala325=	synonymous_variant	3/3	1	NM_001371904.1	P1
APOA5	ENST00000433069.2	c.975C>T	p.Ala325=	synonymous_variant	4/4	1		P1
APOA5	ENST00000673688.1	c.1059C>T	p.Ala353=	synonymous_variant	3/3
APOA5	ENST00000542499.5	c.975C>T	p.Ala325=	synonymous_variant	4/4	5		P1

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 511 AN: 152244 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.000847 AC: 213 AN: 251376 Hom.: 0 AF XY: 0.000699 AC XY: 95 AN XY: 135902

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000341 AC: 498 AN: 1461892 Hom.: 2 Cov.: 34 AF XY: 0.000283 AC XY: 206 AN XY: 727248

Gnomad4 AFR exome AF: 0.0126

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.00337 AC: 513 AN: 152362 Hom.: 3 Cov.: 34 AF XY: 0.00341 AC XY: 254 AN XY: 74516

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00167 Hom.: 1

Bravo AF: 0.00402

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 17, 2017	Variant summary: The APOA5 c.975C>T (p.Ala325Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of multiple ESEs. However, these predictions have yet to be confirmed by functional studies. This variant was found in 131/121182 control chromosomes from ExAC, predominantly observed in the African subpopulation at a frequency of 0.012317 (128/10392). This frequency is about 616 times the estimated maximal expected allele frequency of a pathogenic APOA5 variant (0.00002), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Taken together, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.7
Dann	Benign	0.69

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

LitVar

Other links and lift over

dbSNP: rs137942813; hg19: chr11-116660970;