Genetic Variant METRNL:p.Ser99Leu (chr17-83085063-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001004431.3(METRNL):c.296C>T(p.Ser99Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

METRNL
NM_001004431.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.88

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07310939).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METRNL	NM_001004431.3 link	c.296C>T	p.Ser99Leu	missense_variant	Exon 2 of 4	ENST00000320095.12	NP_001004431.1	Q641Q3-1
METRNL	NM_001363853.2 link	c.50C>T	p.Ser17Leu	missense_variant	Exon 3 of 5		NP_001350782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
METRNL	ENST00000320095.12 link	c.296C>T	p.Ser99Leu	missense_variant	Exon 2 of 4	1	NM_001004431.3	ENSP00000315731.6	Q641Q3-1
METRNL	ENST00000571814.1 link	c.50C>T	p.Ser17Leu	missense_variant	Exon 1 of 3	1		ENSP00000460798.1	Q641Q3-2
METRNL	ENST00000570778.5 link	c.50C>T	p.Ser17Leu	missense_variant	Exon 2 of 4	5		ENSP00000458566.1	Q641Q3-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251026

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135816

show subpopulations

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 SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461574

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.296C>T (p.S99L) alteration is located in exon 2 (coding exon 2) of the METRNL gene. This alteration results from a C to T substitution at nucleotide position 296, causing the serine (S) at amino acid position 99 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.19

T;.;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.84

T;.;T

M_CAP

Benign

0.0086

MetaRNN

Benign

0.073

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;.

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.8

D;.;.

REVEL

Benign

0.061

Sift

Benign

0.079

T;.;.

Sift4G

Benign

0.12

T;T;T

Polyphen

0.025

B;.;.

Vest4

0.089

MutPred

0.37

Loss of sheet (P = 0.0817);.;.;

MVP

0.043

MPC

0.52

ClinPred

0.16

GERP RS

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.49

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over