17-83085192-A-G

Position:

• chr17-83085192-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000320095.12(METRNL):​c.425A>G​(p.Gln142Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,611,070 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (49 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (29 hom.)
• Consequence: METRNL ENST00000320095.12 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.637

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035634637).
• BP6: Variant 17-83085192-A-G is Benign according to our data. Variant chr17-83085192-A-G is described in ClinVar as [Benign]. Clinvar id is 768924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0127 (1940/152312) while in subpopulation AFR AF= 0.0435 (1806/41564). AF 95% confidence interval is 0.0418. There are 49 homozygotes in gnomad4. There are 923 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METRNL	NM_001004431.3	c.425A>G	p.Gln142Arg	missense_variant	2/4	ENST00000320095.12	NP_001004431.1
METRNL	NM_001363853.2	c.179A>G	p.Gln60Arg	missense_variant	3/5		NP_001350782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
METRNL	ENST00000320095.12	c.425A>G	p.Gln142Arg	missense_variant	2/4	1	NM_001004431.3	ENSP00000315731.6
METRNL	ENST00000571814.1	c.179A>G	p.Gln60Arg	missense_variant	1/3	1		ENSP00000460798.1
METRNL	ENST00000570778.5	c.179A>G	p.Gln60Arg	missense_variant	2/4	5		ENSP00000458566.1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1936 AN: 152194 Hom.: 48 Cov.: 33

Gnomad AFR AF: 0.0435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00329 AC: 817 AN: 248532 Hom.: 23 AF XY: 0.00249 AC XY: 335 AN XY: 134800

Gnomad AFR exome AF: 0.0449

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00122 AC: 1782 AN: 1458758 Hom.: 29 Cov.: 36 AF XY: 0.00103 AC XY: 746 AN XY: 725412

Gnomad4 AFR exome AF: 0.0411

Gnomad4 AMR exome AF: 0.00245

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000945

Gnomad4 OTH exome AF: 0.00279

GnomAD4 genome AF: 0.0127 AC: 1940 AN: 152312 Hom.: 49 Cov.: 33 AF XY: 0.0124 AC XY: 923 AN XY: 74474

Gnomad4 AFR AF: 0.0435

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00281 Hom.: 8

Bravo AF: 0.0146

ESP6500AA AF: 0.0463 AC: 204

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00390 AC: 473

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.74
DANN	Benign	0.37
DEOGEN2	Benign	0.017	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.53	T;.;T
MetaRNN	Benign	0.0036	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.54	N;.;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.78	N;.;.
REVEL	Benign	0.011
Sift	Benign	0.75	T;.;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.034
MVP		0.043
MPC		0.58
ClinPred		0.00093	T
GERP RS		-4.4
Varity_R		0.021
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs75438321; hg19: chr17-81043068;