chr16-715699-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024042.4(METRN):​c.220C>T​(p.Pro74Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,394,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000088 ( 0 hom. )

Consequence

METRN
NM_024042.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.16
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
METRNNM_024042.4 linkc.220C>T p.Pro74Ser missense_variant Exon 2 of 4 ENST00000568223.7 NP_076947.1 Q9UJH8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
METRNENST00000568223.7 linkc.220C>T p.Pro74Ser missense_variant Exon 2 of 4 1 NM_024042.4 ENSP00000455068.1 Q9UJH8
METRNENST00000219542.3 linkc.172C>T p.Pro58Ser missense_variant Exon 2 of 3 2 ENSP00000219542.3 J3KMW6
METRNENST00000567076.5 linkc.58C>T p.Pro20Ser missense_variant Exon 1 of 4 5 ENSP00000459900.1 I3L2T3
METRNENST00000570132.1 linkn.105-177C>T intron_variant Intron 1 of 3 3 ENSP00000456647.1 H3BSC8

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
151950
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
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
GnomAD3 exomes
AF:
0.0000786
AC:
3
AN:
38152
Hom.:
0
AF XY:
0.0000426
AC XY:
1
AN XY:
23494
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000536
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000885
AC:
11
AN:
1242958
Hom.:
0
Cov.:
31
AF XY:
0.00000818
AC XY:
5
AN XY:
611072
show subpopulations
Gnomad4 AFR exome
AF:
0.000122
Gnomad4 AMR exome
AF:
0.000248
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:
0.00000297
Gnomad4 OTH exome
AF:
0.0000198
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
151950
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74228
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.0000656
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
Bravo
AF:
0.0000718
ExAC
AF:
0.0000274
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 26, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.220C>T (p.P74S) 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 220, causing the proline (P) at amino acid position 74 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
Benign
0.070
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
11
DANN
Benign
0.82
DEOGEN2
Benign
0.0051
T;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.064
N
LIST_S2
Benign
0.35
T;T
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.0035
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.070
N;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-1.0
N;N
REVEL
Benign
0.012
Sift
Benign
0.66
T;T
Sift4G
Benign
0.24
T;T
Polyphen
0.0020
B;.
Vest4
0.023
MutPred
0.23
Gain of phosphorylation at P74 (P = 0.035);.;
MVP
0.040
MPC
0.27
ClinPred
0.025
T
GERP RS
-2.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.027
gMVP
0.26

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.21
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.21
Position offset: 5

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.

Other links and lift over

dbSNP: rs754921151; hg19: chr16-765699; API