Genetic Variant METRNL:p.Pro28Leu (chr17-83079898-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001004431.3(METRNL):c.83C>T(p.Pro28Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000617 in 145,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

METRNL
NM_001004431.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0950

Publications

0 publications found

Variant links:

Genes affected

METRNL (HGNC:27584): (meteorin like, glial cell differentiation regulator) Predicted to enable hormone activity. Predicted to be involved in several processes, including brown fat cell differentiation; energy homeostasis; and positive regulation of brown fat cell differentiation. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

METRNL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.06951091).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004431.3. 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
	METRNL	NM_001004431.3	MANE Select	c.83C>T	p.Pro28Leu	missense	Exon 1 of 4	NP_001004431.1	Q641Q3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METRNL	ENST00000320095.12	TSL:1 MANE Select	c.83C>T	p.Pro28Leu	missense	Exon 1 of 4	ENSP00000315731.6	Q641Q3-1

Frequencies

GnomAD3 genomes

AF:

0.0000617

AC:

AN:

145830

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000542

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

AF XY:

0.00

Gnomad AMR exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

844668

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

391802

African (AFR)

AF:

0.00

AC:

AN:

15954

American (AMR)

AF:

0.00

AC:

AN:

1442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5488

East Asian (EAS)

AF:

0.00

AC:

AN:

4152

South Asian (SAS)

AF:

0.00

AC:

AN:

17378

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1692

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

768728

Other (OTH)

AF:

0.00

AC:

AN:

27974

GnomAD4 genome

AF:

0.0000617

AC:

AN:

145930

Hom.:

Cov.:

AF XY:

0.0000422

AC XY:

AN XY:

71028

show subpopulations

African (AFR)

AF:

0.0000246

AC:

AN:

40710

American (AMR)

AF:

0.000541

AC:

AN:

14782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3378

East Asian (EAS)

AF:

0.00

AC:

AN:

4922

South Asian (SAS)

AF:

0.00

AC:

AN:

4760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65670

Other (OTH)

AF:

0.00

AC:

AN:

2036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000178

ExAC

AF:

0.000170

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

0.16

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0092

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0098

LIST_S2

Benign

0.30

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.070

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.32

PhyloP100

0.095

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.90

REVEL

Benign

0.043

Sift

Uncertain

0.023

Sift4G

Benign

0.49

Polyphen

0.0

Vest4

0.16

MutPred

0.28

Loss of glycosylation at P28 (P = 4e-04)

MVP

0.043

MPC

1.4

ClinPred

0.40

GERP RS

-1.7

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.043

gMVP

0.18

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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