22-36141225-C-T

Variant names:

• chr22-36141225-C-T
• rs774322767
• NM_145639.2:c.971G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_145639.2(APOL3):​c.971G>A​(p.Arg324His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,613,644 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R324S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: APOL3 NM_145639.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.41
• Publications: 1 publications found

Genes affected

APOL3 (HGNC:14868): (apolipoprotein L3) This gene is a member of the apolipoprotein L gene family, and it is present in a cluster with other family members on chromosome 22. The encoded protein is found in the cytoplasm, where it may affect the movement of lipids, including cholesterol, and/or allow the binding of lipids to organelles. In addition, expression of this gene is up-regulated by tumor necrosis factor-alpha in endothelial cells lining the normal and atherosclerotic iliac artery and aorta. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21498987).
• BP6: Variant 22-36141225-C-T is Benign according to our data. Variant chr22-36141225-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2211018.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145639.2. 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
	APOL3	NM_145639.2	MANE Select	c.971G>A	p.Arg324His	missense	Exon 4 of 4	NP_663614.1	O95236-2
	APOL3	NM_145640.2		c.1184G>A	p.Arg395His	missense	Exon 3 of 3	NP_663615.1	O95236-1
	APOL3	NM_001393587.1		c.974G>A	p.Arg325His	missense	Exon 5 of 5	NP_001380516.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOL3	ENST00000424878.4	TSL:1 MANE Select	c.971G>A	p.Arg324His	missense	Exon 4 of 4	ENSP00000415779.3	O95236-2
	APOL3	ENST00000349314.7	TSL:1	c.1184G>A	p.Arg395His	missense	Exon 3 of 3	ENSP00000344577.2	O95236-1
	APOL3	ENST00000361710.6	TSL:1	c.584G>A	p.Arg195His	missense	Exon 4 of 4	ENSP00000355164.2	O95236-3

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152128 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000877 AC: 22 AN: 250938 AF XY: 0.0000959

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: 0.0000463

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000115 AC: 168 AN: 1461516 Hom.: 0 Cov.: 29 AF XY: 0.000111 AC XY: 81 AN XY: 727058

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

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

European-Non Finnish (NFE) AF: 0.000137 AC: 152 AN: 1111766

Other (OTH) AF: 0.0000663 AC: 4 AN: 60376

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152128 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74320

African (AFR) AF: 0.0000966 AC: 4 AN: 41420

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68016

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000153 Hom.: 0

Bravo AF: 0.000151

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0010
DANN	Benign	0.83
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0068	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		-5.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.017
Sift	Benign	0.57	T
Sift4G	Benign	0.55	T
Polyphen		0.0010	B
Vest4		0.051
MutPred		0.57		Loss of MoRF binding (P = 0.0514)
MVP		0.095
MPC		0.18
ClinPred		0.010	T
GERP RS		-5.4
Varity_R		0.014
gMVP		0.076
Mutation Taster		=100/0	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: rs774322767; hg19: chr22-36537273; COSMIC: COSV100652121; COSMIC: COSV100652121;