Genetic Variant APLN:p.Gly37Ser (chrX-129648751-C-T) – 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.109G>A(p.Gly37Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000565 in 1,061,749 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000057 ( 0 hom. 3 hem. )

Consequence

APLN
NM_017413.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.08

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:

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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=0.15705827).

BS2

High Hemizygotes in GnomAdExome4 at 3 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.109G>A	p.Gly37Ser	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.109G>A	p.Gly37Ser	missense	Exon 2 of 3	ENSP00000391800.2	Q9ULZ1
APLN	ENST00000865540.1		c.394G>A	p.Gly132Ser	missense	Exon 2 of 3	ENSP00000535599.1
ENSG00000308713	ENST00000835926.1		n.344-2772C>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000819

AC:

AN:

122064

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000495

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000565

AC:

AN:

1061749

Hom.:

Cov.:

AF XY:

0.00000869

AC XY:

AN XY:

345373

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25341

American (AMR)

AF:

0.000102

AC:

AN:

29345

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18709

East Asian (EAS)

AF:

0.0000359

AC:

AN:

27840

South Asian (SAS)

AF:

0.0000200

AC:

AN:

50070

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38055

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3985

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

823698

Other (OTH)

AF:

0.00

AC:

AN:

44706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000358

AC:

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

Benign

0.074

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.51

M_CAP

Benign

0.0093

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

PhyloP100

1.1

PrimateAI

Benign

0.47

Sift4G

Benign

0.12

Polyphen

0.42

Vest4

0.35

MutPred

0.25

Loss of sheet (P = 0.0457)

MVP

0.69

ClinPred

0.30

GERP RS

3.9

Varity_R

0.15

gMVP

0.12

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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