17-83085063-C-T

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

1
18

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]

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
METRNLNM_001004431.3 linkc.296C>T p.Ser99Leu missense_variant Exon 2 of 4 ENST00000320095.12 NP_001004431.1 Q641Q3-1
METRNLNM_001363853.2 linkc.50C>T p.Ser17Leu missense_variant Exon 3 of 5 NP_001350782.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
METRNLENST00000320095.12 linkc.296C>T p.Ser99Leu missense_variant Exon 2 of 4 1 NM_001004431.3 ENSP00000315731.6 Q641Q3-1
METRNLENST00000571814.1 linkc.50C>T p.Ser17Leu missense_variant Exon 1 of 3 1 ENSP00000460798.1 Q641Q3-2
METRNLENST00000570778.5 linkc.50C>T p.Ser17Leu missense_variant Exon 2 of 4 5 ENSP00000458566.1 Q641Q3-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152244
Hom.:
0
Cov.:
33
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:
2
AN:
251026
Hom.:
0
AF XY:
0.0000147
AC XY:
2
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:
13
AN:
1461574
Hom.:
0
Cov.:
30
AF XY:
0.00000825
AC XY:
6
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:
1
AN:
152244
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
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
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
15
DANN
Benign
0.97
DEOGEN2
Benign
0.19
T;.;.
Eigen
Benign
-0.88
Eigen_PC
Benign
-0.96
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.84
T;.;T
M_CAP
Benign
0.0086
T
MetaRNN
Benign
0.073
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L;.;.
PrimateAI
Benign
0.32
T
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
T
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.

Other links and lift over

dbSNP: rs766505886; hg19: chr17-81042939; COSMIC: COSV105198987; API