rs746312873

Variant names:

• chr22-36257323-C-A
• rs746312873
• NM_003661.4:c.103C>A

Your query was ambiguous. Multiple possible variants found:

• chr22-36257323-C-A
• chr22-36257323-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003661.4(APOL1):​c.103C>A​(p.Gln35Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: APOL1 NM_003661.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.375
• Publications: 0 publications found

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]

APOL1 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 4, susceptibility to

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04140398).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003661.4. 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
	APOL1	NM_003661.4	MANE Select	c.103C>A	p.Gln35Lys	missense	Exon 4 of 6	NP_003652.2
	APOL1	NM_145343.3		c.151C>A	p.Gln51Lys	missense	Exon 5 of 7	NP_663318.1	O14791-2
	APOL1	NM_001136540.2		c.103C>A	p.Gln35Lys	missense	Exon 4 of 6	NP_001130012.1	O14791-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOL1	ENST00000397278.8	TSL:1 MANE Select	c.103C>A	p.Gln35Lys	missense	Exon 4 of 6	ENSP00000380448.4	O14791-1
	APOL1	ENST00000319136.8	TSL:1	c.151C>A	p.Gln51Lys	missense	Exon 5 of 7	ENSP00000317674.4	O14791-2
	APOL1	ENST00000438034.6	TSL:4	c.190C>A	p.Gln64Lys	missense	Exon 5 of 7	ENSP00000404525.2	B1AH94

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461788 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111912

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.028
DANN	Benign	0.50
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.000080	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.38
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.036
Sift	Benign	0.42	T
Sift4G	Benign	0.57	T
Polyphen		0.0040	B
Vest4		0.18
MutPred		0.22		Gain of ubiquitination at Q35 (P = 0.0085)
MVP		0.19
MPC		0.073
ClinPred		0.050	T
GERP RS		-0.69
Varity_R		0.028
gMVP		0.047
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs746312873; hg19: chr22-36653369;