Genetic Variant METRN:p.Ala48Val (chr16-715622-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024042.4(METRN):c.143C>T(p.Ala48Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000392 in 1,274,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 0.0000039 ( 0 hom. )

Consequence

METRN
NM_024042.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.669

Variant links:

Genes affected

METRN (HGNC:14151): (meteorin, glial cell differentiation regulator) Meteorin regulates glial cell differentiation and promotes the formation of axonal networks during neurogenesis (Nishino et al., 2004 [PubMed 15085178]).[supplied by OMIM, Mar 2008]

METRN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.022659719).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METRN	NM_024042.4 link	c.143C>T	p.Ala48Val	missense_variant	Exon 2 of 4	ENST00000568223.7	NP_076947.1	Q9UJH8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
METRN	ENST00000568223.7 link	c.143C>T	p.Ala48Val	missense_variant	Exon 2 of 4	1	NM_024042.4	ENSP00000455068.1	Q9UJH8
METRN	ENST00000219542.3 link	c.95C>T	p.Ala32Val	missense_variant	Exon 2 of 3	2		ENSP00000219542.3	J3KMW6
METRN	ENST00000570132.1 link	n.104+229C>T		intron_variant	Intron 1 of 3	3		ENSP00000456647.1	H3BSC8
METRN	ENST00000567076.5 link	c.-20C>T		upstream_gene_variant		5		ENSP00000459900.1	I3L2T3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000790

AC:

AN:

63310

Hom.:

AF XY:

0.0000536

AC XY:

AN XY:

37314

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000285

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000433

Gnomad SAS exome

AF:

0.0000853

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000392

AC:

AN:

1274564

Hom.:

Cov.:

AF XY:

0.00000159

AC XY:

AN XY:

628296

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000988

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000357

Gnomad4 SAS exome

AF:

0.0000154

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.73e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000192

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.143C>T (p.A48V) alteration is located in exon 2 (coding exon 2) of the METRN gene. This alteration results from a C to T substitution at nucleotide position 143, causing the alanine (A) at amino acid position 48 to be replaced by a valine (V). 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

0.10

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0090

T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.65

T;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.023

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;.

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.16

N;N

REVEL

Benign

0.023

Sift

Benign

0.17

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.0090

B;.

Vest4

0.12

MutPred

0.28

Loss of helix (P = 0.0626);.;

MVP

0.030

MPC

0.26

ClinPred

0.032

GERP RS

0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.34

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

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