17-83094264-G-A

Position:

• chr17-83094264-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000320095.12(METRNL):​c.625G>A​(p.Gly209Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: METRNL ENST00000320095.12 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METRNL	NM_001004431.3	c.625G>A	p.Gly209Ser	missense_variant	4/4	ENST00000320095.12	NP_001004431.1
METRNL	NM_001363853.2	c.379G>A	p.Gly127Ser	missense_variant	5/5		NP_001350782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
METRNL	ENST00000320095.12	c.625G>A	p.Gly209Ser	missense_variant	4/4	1	NM_001004431.3	ENSP00000315731.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2023

The c.625G>A (p.G209S) alteration is located in exon 4 (coding exon 4) of the METRNL gene. This alteration results from a G to A substitution at nucleotide position 625, causing the glycine (G) at amino acid position 209 to be replaced by a serine (S). 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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;.;D;T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.6	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.4	D;.;.;.
REVEL	Uncertain	0.61
Sift	Benign	0.075	T;.;.;.
Sift4G	Benign	0.070	T;T;T;D
Polyphen		1.0	D;.;.;.
Vest4		0.91
MutPred		0.80		Gain of disorder (P = 0.0169);.;.;.;
MVP		0.50
MPC		1.5
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.50
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-81052009;