Variant 11-61770282-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001127392.3(MYRF):c.497T>C(p.Leu166Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MYRF
NM_001127392.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.15

Variant links:

Genes affected

MYRF (HGNC:1181): (myelin regulatory factor) This gene encodes a transcription factor that is required for central nervous system myelination and may regulate oligodendrocyte differentiation. It is thought to act by increasing the expression of genes that effect myelin production but may also directly promote myelin gene expression. Loss of a similar gene in mouse models results in severe demyelination. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

MYRF links:

TMEM258 (HGNC:1164): (transmembrane protein 258) Involved in protein N-linked glycosylation. Located in endoplasmic reticulum. Part of oligosaccharyltransferase I complex. [provided by Alliance of Genome Resources, Apr 2022]

TMEM258 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYRF. . Gene score misZ: 3.2927 (greater than the threshold 3.09). Trascript score misZ: 3.5469 (greater than threshold 3.09). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. GenCC has associacion of the gene with encephalitis/encephalopathy, mild, with reversible myelin vacuolization, cardiac-urogenital syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYRF	NM_001127392.3 link	c.497T>C	p.Leu166Pro	missense_variant	5/27	ENST00000278836.10	NP_001120864.1	Q9Y2G1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYRF	ENST00000278836.10 link	c.497T>C	p.Leu166Pro	missense_variant	5/27	1	NM_001127392.3	ENSP00000278836.4	Q9Y2G1-1
MYRF	ENST00000265460.9 link	c.470T>C	p.Leu157Pro	missense_variant	5/26	1		ENSP00000265460.5	Q9Y2G1-2
MYRF	ENST00000675319.1 link	c.105-1218T>C		intron_variant				ENSP00000502795.1	A0A6Q8PHM1
TMEM258	ENST00000535042.1 link	n.649-1509A>G		intron_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1456192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724238

Gnomad4 AFR exome

AF:

0.00

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:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.095

T;.

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.56

D;D

MetaSVM

Benign

-1.1

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.5

D;D

REVEL

Benign

0.20

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.028

D;T

Polyphen

0.99

D;D

Vest4

0.74

MutPred

0.27

Gain of loop (P = 0.024);.;

MVP

0.17

MPC

0.58

ClinPred

0.93

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.50

gMVP

0.53

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over