11-61770306-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Moderate BP6_Moderate BS1 BS2

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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R174C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (1 hom.)
• Consequence: MYRF NM_001127392.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.82

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]

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYRF
• 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 criteria_provided_single_submitter, 1 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 GnomAd at 81 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYRF	NM_001127392.3	c.521G>A	p.Arg174His	missense_variant	5/27	ENST00000278836.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYRF	ENST00000278836.10	c.521G>A	p.Arg174His	missense_variant	5/27	1	NM_001127392.3	P2
MYRF	ENST00000265460.9	c.494G>A	p.Arg165His	missense_variant	5/26	1		A2
MYRF	ENST00000675319.1	c.106-1194G>A		intron_variant
TMEM258	ENST00000535042.1	n.649-1533C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 151850 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.000675 AC XY: 84 AN XY: 124362

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.: 1 Cov.: 33 AF XY: 0.000849 AC XY: 612 AN XY: 721176

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: 81 AN: 151850 Hom.: 0 Cov.: 32 AF XY: 0.000485 AC XY: 36 AN XY: 74156

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.: 0

Bravo AF: 0.000461

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000850 AC: 102

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MYRF-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2022

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	T
BayesDel_noAF	Benign	-0.34
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.036	T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.088	T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	0.93	D;D
PrimateAI	Pathogenic	0.85	D
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	T
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

Other links and lift over

dbSNP: rs200370195; hg19: chr11-61537778; COSMIC: COSV99606896; COSMIC: COSV99606896;