NM_001127392.3:c.521G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001127392.3(MYRF):c.521G>A(p.Arg174His) variant causes a missense change. The variant allele was found at a frequency of 0.000801 in 1,602,592 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 1 hom. )

Consequence

MYRF
NM_001127392.3 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.82

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PP2

Missense variant in the MYRF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 3.2927 (above the threshold of 3.09). Trascript score misZ: 3.5469 (above the threshold of 3.09). GenCC associations: The gene is linked to encephalitis/encephalopathy, mild, with reversible myelin vacuolization, cardiac-urogenital syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.08777475).

BP6

Variant 11-61770306-G-A is Benign according to our data. Variant chr11-61770306-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3051447.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000533 (81/151850) while in subpopulation NFE AF= 0.000972 (66/67932). AF 95% confidence interval is 0.000783. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 81 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYRF	NM_001127392.3 link	c.521G>A	p.Arg174His	missense_variant	Exon 5 of 27	ENST00000278836.10	NP_001120864.1	Q9Y2G1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYRF	ENST00000278836.10 link	c.521G>A	p.Arg174His	missense_variant	Exon 5 of 27	1	NM_001127392.3	ENSP00000278836.4	Q9Y2G1-1
MYRF	ENST00000265460.9 link	c.494G>A	p.Arg165His	missense_variant	Exon 5 of 26	1		ENSP00000265460.5	Q9Y2G1-2
MYRF	ENST00000675319.1 link	c.105-1194G>A		intron_variant	Intron 1 of 22			ENSP00000502795.1	A0A6Q8PHM1
TMEM258	ENST00000535042.1 link	n.649-1533C>T		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.000533

AC:

AN:

151850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000851

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000972

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000642

AC:

146

AN:

227280

Hom.:

AF XY:

0.000675

AC XY:

AN XY:

124362

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000120

Gnomad ASJ exome

AF:

0.000626

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00109

Gnomad NFE exome

AF:

0.00112

Gnomad OTH exome

AF:

0.000535

GnomAD4 exome

AF:

0.000829

AC:

1202

AN:

1450742

Hom.:

Cov.:

AF XY:

0.000849

AC XY:

612

AN XY:

721176

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.000540

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00107

Gnomad4 NFE exome

AF:

0.000974

Gnomad4 OTH exome

AF:

0.000636

GnomAD4 genome

AF:

0.000533

AC:

AN:

151850

Hom.:

Cov.:

AF XY:

0.000485

AC XY:

AN XY:

74156

show subpopulations

Gnomad4 AFR

AF:

0.0000968

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000851

Gnomad4 NFE

AF:

0.000972

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000938

Hom.:

Bravo

AF:

0.000461

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000850

AC:

102

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

MYRF-related disorder

Benign:1

Jul 11, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.036

T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.088

T;T

MetaSVM

Benign

-0.85

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.20

Sift

Uncertain

0.013

D;D

Sift4G

Uncertain

0.059

T;T

Polyphen

1.0

D;D

Vest4

0.53

MVP

0.22

MPC

0.57

ClinPred

0.11

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.15

gMVP

0.18

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