11-116791691-G-C

Variant names:

• chr11-116791691-G-C
• rs3135506
• NM_001371904.1:c.56C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001371904.1(APOA5):​c.56C>G​(p.Ser19Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0624 in 1,607,778 control chromosomes in the GnomAD database, including 3,555 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S19L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.065 (352 hom., cov: 34)
  • Exomes 𝑓: 0.062 (3203 hom.)
• Consequence: APOA5 NM_001371904.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 1.58
• Publications: 366 publications found

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]

APOA5 Gene-Disease associations (from GenCC):

• hypertriglyceridemia 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hyperlipoproteinemia type V

  Inheritance: AD, SD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018840134).
• BP6: Variant 11-116791691-G-C is Benign according to our data. Variant chr11-116791691-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 4403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371904.1. 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
	APOA5	NM_001371904.1	MANE Select	c.56C>G	p.Ser19Trp	missense	Exon 2 of 3	NP_001358833.1	Q6Q788
	APOA5	NM_001166598.2		c.56C>G	p.Ser19Trp	missense	Exon 3 of 4	NP_001160070.1	A0A0B4RUS7
	APOA5	NM_052968.5		c.56C>G	p.Ser19Trp	missense	Exon 3 of 4	NP_443200.2	Q6Q788

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOA5	ENST00000227665.9	TSL:1 MANE Select	c.56C>G	p.Ser19Trp	missense	Exon 2 of 3	ENSP00000227665.4	Q6Q788
	APOA5	ENST00000433069.2	TSL:1	c.56C>G	p.Ser19Trp	missense	Exon 3 of 4	ENSP00000399701.2	Q6Q788
	APOA5	ENST00000673688.1		c.56C>G	p.Ser19Trp	missense	Exon 2 of 3	ENSP00000501141.1	A0A669KB69

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 9872 AN: 152200 Hom.: 349 Cov.: 34

Gnomad AFR AF: 0.0619

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0405

Gnomad FIN AF: 0.0551

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0628

Gnomad OTH AF: 0.0779

GnomAD2 exomes AF: 0.0684 AC: 16228 AN: 237114 AF XY: 0.0645

Gnomad AFR exome AF: 0.0635

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.0681

Gnomad EAS exome AF: 0.000286

Gnomad FIN exome AF: 0.0608

Gnomad NFE exome AF: 0.0640

Gnomad OTH exome AF: 0.0701

GnomAD4 exome AF: 0.0621 AC: 90359 AN: 1455460 Hom.: 3203 Cov.: 33 AF XY: 0.0610 AC XY: 44118 AN XY: 723514

African (AFR) AF: 0.0645 AC: 2148 AN: 33286

American (AMR) AF: 0.147 AC: 6413 AN: 43700

Ashkenazi Jewish (ASJ) AF: 0.0653 AC: 1697 AN: 25982

East Asian (EAS) AF: 0.000559 AC: 22 AN: 39364

South Asian (SAS) AF: 0.0387 AC: 3297 AN: 85286

European-Finnish (FIN) AF: 0.0626 AC: 3319 AN: 52982

Middle Eastern (MID) AF: 0.0542 AC: 312 AN: 5760

European-Non Finnish (NFE) AF: 0.0627 AC: 69507 AN: 1108956

Other (OTH) AF: 0.0606 AC: 3644 AN: 60144

GnomAD4 genome AF: 0.0649 AC: 9890 AN: 152318 Hom.: 352 Cov.: 34 AF XY: 0.0642 AC XY: 4778 AN XY: 74480

African (AFR) AF: 0.0619 AC: 2574 AN: 41574

American (AMR) AF: 0.114 AC: 1737 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 228 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0408 AC: 197 AN: 4832

European-Finnish (FIN) AF: 0.0551 AC: 585 AN: 10616

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0628 AC: 4275 AN: 68026

Other (OTH) AF: 0.0776 AC: 164 AN: 2114

Alfa AF: 0.0542 Hom.: 191

Bravo AF: 0.0704

TwinsUK AF: 0.0620 AC: 230

ALSPAC AF: 0.0643 AC: 248

ESP6500AA AF: 0.0611 AC: 269

ESP6500EA AF: 0.0649 AC: 558

ExAC AF: 0.0620 AC: 7527

Asia WGS AF: 0.0300 AC: 104 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Familial type 5 hyperlipoproteinemia;C5444012:Hypertriglyceridemia 1 (1)
-	-	-	Hypertriglyceridemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.6
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.43
MPC		1.5
ClinPred		0.017	T
GERP RS		5.4
PromoterAI		-0.0094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.098
gMVP		0.42
Mutation Taster		=99/1	polymorphism (auto)

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: rs3135506; hg19: chr11-116662407; COSMIC: COSV57062904; COSMIC: COSV57062904;