3-195579418-A-G

Position:

• chr3-195579418-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001647.4(APOD):​c.44T>C​(p.Phe15Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,614,068 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (28 hom.)
• Consequence: APOD NM_001647.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.31

Genes affected

APOD (HGNC:612): (apolipoprotein D) This gene encodes a component of high density lipoprotein that has no marked similarity to other apolipoprotein sequences. It has a high degree of homology to plasma retinol-binding protein and other members of the alpha 2 microglobulin protein superfamily of carrier proteins, also known as lipocalins. This glycoprotein is closely associated with the enzyme lecithin:cholesterol acyltransferase - an enzyme involved in lipoprotein metabolism. [provided by RefSeq, Aug 2008]

APOD (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046077073).
• BP6: Variant 3-195579418-A-G is Benign according to our data. Variant chr3-195579418-A-G is described in ClinVar as [Benign]. Clinvar id is 769625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOD	NM_001647.4	c.44T>C	p.Phe15Ser	missense_variant	2/5	ENST00000343267.8	NP_001638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOD	ENST00000343267.8	c.44T>C	p.Phe15Ser	missense_variant	2/5	1	NM_001647.4	ENSP00000345179.3

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 641 AN: 152212 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00578

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00422 AC: 1056 AN: 250390 Hom.: 7 AF XY: 0.00451 AC XY: 611 AN XY: 135542

Gnomad AFR exome AF: 0.000820

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00752

Gnomad NFE exome AF: 0.00593

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00465 AC: 6802 AN: 1461738 Hom.: 28 Cov.: 31 AF XY: 0.00455 AC XY: 3310 AN XY: 727178

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00458

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.00711

Gnomad4 NFE exome AF: 0.00523

Gnomad4 OTH exome AF: 0.00442

GnomAD4 genome AF: 0.00421 AC: 641 AN: 152330 Hom.: 3 Cov.: 33 AF XY: 0.00443 AC XY: 330 AN XY: 74482

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00678

Gnomad4 NFE AF: 0.00578

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00536 Hom.: 2

Bravo AF: 0.00371

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00417 AC: 506

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00687

EpiControl AF: 0.00735

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 29, 2018	- -

APOD-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T;.;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.43	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D;D;D
Sift4G	Benign	0.25	T;.;.
Polyphen		0.0020	B;.;.
Vest4		0.31
MVP		0.33
MPC		0.23
ClinPred		0.036	T
GERP RS		1.6
Varity_R		0.14
gMVP		0.40

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: rs5952; hg19: chr3-195306289;