NM_001371904.1:c.973G>A

Variant names:

• chr11-116790256-C-T
• rs751582219
• NM_001371904.1:c.973G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001371904.1(APOA5):​c.973G>A​(p.Ala325Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A325S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: APOA5 NM_001371904.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.190
• Publications: 1 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05507174).
• BS2: High AC in GnomAdExome4 at 15 AD,SD gene.

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.973G>A	p.Ala325Thr	missense	Exon 3 of 3	NP_001358833.1	Q6Q788
	APOA5	NM_001166598.2		c.973G>A	p.Ala325Thr	missense	Exon 4 of 4	NP_001160070.1	A0A0B4RUS7
	APOA5	NM_052968.5		c.973G>A	p.Ala325Thr	missense	Exon 4 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.973G>A	p.Ala325Thr	missense	Exon 3 of 3	ENSP00000227665.4	Q6Q788
	APOA5	ENST00000433069.2	TSL:1	c.973G>A	p.Ala325Thr	missense	Exon 4 of 4	ENSP00000399701.2	Q6Q788
	APOA5	ENST00000673688.1		c.1057G>A	p.Ala353Thr	missense	Exon 3 of 3	ENSP00000501141.1	A0A669KB69

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251362 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000103 AC: 15 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11 AN XY: 727246

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

American (AMR) AF: 0.00 AC: 0 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: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.19
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.062
Sift	Benign	0.26	T
Sift4G	Uncertain	0.020	D
Polyphen		0.10	B
Vest4		0.092
MutPred		0.22		Gain of glycosylation at A325 (P = 0.0355)
MVP		0.56
MPC		0.50
ClinPred		0.056	T
GERP RS		1.8
Varity_R		0.035
gMVP		0.18
Mutation Taster		=98/2	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: rs751582219; hg19: chr11-116660972; COSMIC: COSV57062411; COSMIC: COSV57062411;