17-83085061-C-G

Variant names:

• chr17-83085061-C-G
• NM_001004431.3:c.294C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001004431.3(METRNL):​c.294C>G​(p.Phe98Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: METRNL NM_001004431.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0930
• Publications: 0 publications found

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]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026551813).

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.294C>G	p.Phe98Leu	missense	Exon 2 of 4	NP_001004431.1	Q641Q3-1
	METRNL	NM_001363853.2		c.48C>G	p.Phe16Leu	missense	Exon 3 of 5	NP_001350782.1	Q641Q3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METRNL	ENST00000320095.12	TSL:1 MANE Select	c.294C>G	p.Phe98Leu	missense	Exon 2 of 4	ENSP00000315731.6	Q641Q3-1
	METRNL	ENST00000571814.1	TSL:1	c.48C>G	p.Phe16Leu	missense	Exon 1 of 3	ENSP00000460798.1	Q641Q3-2
	METRNL	ENST00000570778.5	TSL:5	c.48C>G	p.Phe16Leu	missense	Exon 2 of 4	ENSP00000458566.1	Q641Q3-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461584 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727090

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.1
DANN	Benign	0.61
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.093
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.015
Sift	Benign	0.75	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.052
MutPred		0.25		Gain of loop (P = 0.1069)
MVP		0.068
MPC		0.63
ClinPred		0.029	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
gMVP		0.30
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

hg19: chr17-81042937;