16-715842-G-C

Position:

• chr16-715842-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024042.4(METRN):​c.363G>C​(p.Trp121Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000858 in 1,165,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: METRN NM_024042.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.805

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26112708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METRN	NM_024042.4	c.363G>C	p.Trp121Cys	missense_variant	2/4	ENST00000568223.7	NP_076947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
METRN	ENST00000568223.7	c.363G>C	p.Trp121Cys	missense_variant	2/4	1	NM_024042.4	ENSP00000455068	P2
METRN	ENST00000219542.3	c.315G>C	p.Trp105Cys	missense_variant	2/3	2		ENSP00000219542
METRN	ENST00000567076.5	c.204G>C	p.Trp68Cys	missense_variant	1/4	5		ENSP00000459900
METRN	ENST00000570132.1	c.105-34G>C		intron_variant, NMD_transcript_variant		3		ENSP00000456647

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.58e-7 AC: 1 AN: 1165734 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 562394

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000373

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.363G>C (p.W121C) alteration is located in exon 2 (coding exon 2) of the METRN gene. This alteration results from a G to C substitution at nucleotide position 363, causing the tryptophan (W) at amino acid position 121 to be replaced by a cysteine (C). 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	Pathogenic	0.94
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Benign	0.93
DEOGEN2	Benign	0.020	T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.59	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.76	N;N
REVEL	Benign	0.22
Sift	Benign	0.45	T;T
Sift4G	Benign	0.28	T;T
Polyphen		1.0	D;.
Vest4		0.28
MutPred		0.46		Loss of sheet (P = 0.0104);.;
MVP		0.31
MPC		1.2
ClinPred		0.73	D
GERP RS		3.9
Varity_R		0.22
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-765842;