Genetic Variant NM_024042.4:c.14C>G (chr16-715303-C-G) – 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.14C>G(p.Ala5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,337,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

METRN
NM_024042.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.382

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=0.06758392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METRN	NM_024042.4 link	c.14C>G	p.Ala5Gly	missense_variant	Exon 1 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.14C>G	p.Ala5Gly	missense_variant	Exon 1 of 4	1	NM_024042.4	ENSP00000455068.1	Q9UJH8
METRN	ENST00000570132.1 link	n.14C>G		non_coding_transcript_exon_variant	Exon 1 of 4	3		ENSP00000456647.1	H3BSC8
METRN	ENST00000219542.3 link	c.-35C>G		upstream_gene_variant		2		ENSP00000219542.3	J3KMW6

Frequencies

GnomAD3 genomes

AF:

0.000198

AC:

AN:

151378

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000726

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000759

AC:

AN:

1186328

Hom.:

Cov.:

AF XY:

0.00000517

AC XY:

AN XY:

579768

show subpopulations

Gnomad4 AFR exome

AF:

0.000294

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000423

GnomAD4 genome

AF:

0.000198

AC:

AN:

151486

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

AN XY:

74058

show subpopulations

Gnomad4 AFR

AF:

0.000724

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000185

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14C>G (p.A5G) alteration is located in exon 1 (coding exon 1) of the METRN gene. This alteration results from a C to G substitution at nucleotide position 14, causing the alanine (A) at amino acid position 5 to be replaced by a glycine (G). 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

-0.48

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.66

DEOGEN2

Benign

0.021

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.35

M_CAP

Benign

0.058

MetaRNN

Benign

0.068

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.0

Sift

Benign

0.29

Sift4G

Benign

0.37

Polyphen

0.034

Vest4

0.16

MutPred

0.26

Loss of helix (P = 0.0444);

MVP

0.095

MPC

0.26

ClinPred

0.25

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.040

gMVP

0.23

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