dbSNP rs757193827: APLN:p.Trp55Arg (chrX-129648697-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_017413.5(APLN):c.163T>C(p.Trp55Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,181,147 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000010 ( 0 hom. 4 hem. )

Consequence

APLN
NM_017413.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.57

Publications

1 publications found

Variant links:

Genes affected

APLN (HGNC:16665): (apelin) This gene encodes a peptide that functions as an endogenous ligand for the G-protein coupled apelin receptor. The encoded preproprotein is proteolytically processed into biologically active C-terminal peptide fragments. These peptide fragments activate different tissue specific signaling pathways that regulate diverse biological functions including fluid homeostasis, cardiovascular function and insulin secretion. This protein also functions as a coreceptor for the human immunodeficiency virus 1. [provided by RefSeq, Feb 2016]

APLN links:

ENSG00000308713 (HGNC:):

ENSG00000308713 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23115152).

BS2

High Hemizygotes in GnomAdExome4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017413.5. 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
	APLN	NM_017413.5	MANE Select	c.163T>C	p.Trp55Arg	missense	Exon 2 of 3	NP_059109.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APLN	ENST00000429967.3	TSL:1 MANE Select	c.163T>C	p.Trp55Arg	missense	Exon 2 of 3	ENSP00000391800.2	Q9ULZ1
APLN	ENST00000865540.1		c.448T>C	p.Trp150Arg	missense	Exon 2 of 3	ENSP00000535599.1
ENSG00000308713	ENST00000835926.1		n.344-2826A>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000883

AC:

AN:

113247

Hom.:

Cov.:

show subpopulations

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1067900

Hom.:

Cov.:

AF XY:

0.0000115

AC XY:

AN XY:

346898

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25577

American (AMR)

AF:

0.00

AC:

AN:

30742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18809

East Asian (EAS)

AF:

0.00

AC:

AN:

28376

South Asian (SAS)

AF:

0.00

AC:

AN:

50500

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3920

European-Non Finnish (NFE)

AF:

0.0000121

AC:

AN:

826734

Other (OTH)

AF:

0.0000223

AC:

AN:

44916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000883

AC:

AN:

113247

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35411

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31236

American (AMR)

AF:

0.00

AC:

AN:

10861

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3573

South Asian (SAS)

AF:

0.00

AC:

AN:

2818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6329

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53318

Other (OTH)

AF:

0.00

AC:

AN:

1533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.33

M_CAP

Benign

0.029

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.0

PhyloP100

3.6

PrimateAI

Uncertain

0.64

Sift4G

Benign

0.61

Polyphen

0.019

Vest4

0.39

MutPred

0.25

Gain of methylation at W55 (P = 0.0044)

MVP

0.89

ClinPred

0.91

GERP RS

4.5

Varity_R

0.70

gMVP

0.030

Mutation Taster

=78/22

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over