11-116790676-C-G

Variant names:

• chr11-116790676-C-G
• NM_001371904.1:c.553G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_001371904.1(APOA5):​c.553G>C​(p.Gly185Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G185C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APOA5 NM_001371904.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.159

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-116790676-C-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.36655852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA5	NM_001371904.1	c.553G>C	p.Gly185Arg	missense_variant	Exon 3 of 3	ENST00000227665.9	NP_001358833.1
APOA5	NM_001166598.2	c.553G>C	p.Gly185Arg	missense_variant	Exon 4 of 4		NP_001160070.1
APOA5	NM_052968.5	c.553G>C	p.Gly185Arg	missense_variant	Exon 4 of 4		NP_443200.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOA5	ENST00000227665.9	c.553G>C	p.Gly185Arg	missense_variant	Exon 3 of 3	1	NM_001371904.1	ENSP00000227665.4
APOA5	ENST00000433069.2	c.553G>C	p.Gly185Arg	missense_variant	Exon 4 of 4	1		ENSP00000399701.2
APOA5	ENST00000673688.1	c.637G>C	p.Gly213Arg	missense_variant	Exon 3 of 3			ENSP00000501141.1
APOA5	ENST00000542499.5	c.553G>C	p.Gly185Arg	missense_variant	Exon 4 of 4	5		ENSP00000445002.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460262 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726492

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.058
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.81	.;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.28
Sift	Benign	0.068	T;T
Sift4G	Uncertain	0.023	D;D
Polyphen		0.94	P;P
Vest4		0.31
MutPred		0.39		Gain of MoRF binding (P = 0.0197);Gain of MoRF binding (P = 0.0197);
MVP		0.89
MPC		1.5
ClinPred		0.64	D
GERP RS		4.1
Varity_R		0.20
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-116661392;