rs16996616

Positions:

• chr22-36265845-G-A
• chr22-36265845-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003661.4(APOL1):​c.1009G>A​(p.Asp337Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00543 in 1,614,154 control chromosomes in the GnomAD database, including 329 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.026 (163 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (166 hom.)
• Consequence: APOL1 NM_003661.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.205

Genes affected

APOL1 (HGNC:618): (apolipoprotein L1) This gene encodes a secreted high density lipoprotein which binds to apolipoprotein A-I. Apolipoprotein A-I is a relatively abundant plasma protein and is the major apoprotein of HDL. It is involved in the formation of most cholesteryl esters in plasma and also promotes efflux of cholesterol from cells. This apolipoprotein L family member may play a role in lipid exchange and transport throughout the body, as well as in reverse cholesterol transport from peripheral cells to the liver. Several different transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029411316).
• BP6: Variant 22-36265845-G-A is Benign according to our data. Variant chr22-36265845-G-A is described in ClinVar as [Benign]. Clinvar id is 777703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36265845-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOL1	NM_003661.4	c.1009G>A	p.Asp337Asn	missense_variant	6/6	ENST00000397278.8	NP_003652.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOL1	ENST00000397278.8	c.1009G>A	p.Asp337Asn	missense_variant	6/6	1	NM_003661.4	ENSP00000380448.4

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3918 AN: 152144 Hom.: 162 Cov.: 31

Gnomad AFR AF: 0.0877

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00764 AC: 1921 AN: 251428 Hom.: 72 AF XY: 0.00623 AC XY: 846 AN XY: 135902

Gnomad AFR exome AF: 0.0914

Gnomad AMR exome AF: 0.00503

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00412

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000897

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00330 AC: 4831 AN: 1461892 Hom.: 166 Cov.: 36 AF XY: 0.00304 AC XY: 2209 AN XY: 727246

Gnomad4 AFR exome AF: 0.0888

Gnomad4 AMR exome AF: 0.00568

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00414

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000593

Gnomad4 OTH exome AF: 0.00806

GnomAD4 genome AF: 0.0258 AC: 3929 AN: 152262 Hom.: 163 Cov.: 31 AF XY: 0.0253 AC XY: 1883 AN XY: 74448

Gnomad4 AFR AF: 0.0878

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00645 Hom.: 71

Bravo AF: 0.0296

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0844 AC: 372

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00908 AC: 1103

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.8
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T;T;.;.;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.74	.;.;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.69	N;N;.;.;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.72	N;N;N;N;N
REVEL	Benign	0.031
Sift	Benign	0.057	T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.37	B;B;.;B;B
Vest4		0.038
MVP		0.38
MPC		0.14
ClinPred		0.0052	T
GERP RS		2.1
Varity_R		0.025
gMVP		0.16

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: rs16996616; hg19: chr22-36661891; COSMIC: COSV59869293; COSMIC: COSV59869293;