11-61770486-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_001127392.3(MYRF):c.701C>T(p.Ser234Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000998 in 1,565,352 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (11 hom.)
• Consequence: MYRF NM_001127392.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.31

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 -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYRF
• BP4: Computational evidence support a benign effect (MetaRNN=0.009031802).
• BP6: Variant 11-61770486-C-T is Benign according to our data. Variant chr11-61770486-C-T is described in ClinVar as [Benign]. Clinvar id is 3050477.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00131 (199/152248) while in subpopulation SAS AF= 0.00414 (20/4826). AF 95% confidence interval is 0.00275. There are 1 homozygotes in gnomad4. There are 134 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 199 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYRF	NM_001127392.3	c.701C>T	p.Ser234Phe	missense_variant	5/27	ENST00000278836.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYRF	ENST00000278836.10	c.701C>T	p.Ser234Phe	missense_variant	5/27	1	NM_001127392.3	P2
MYRF	ENST00000265460.9	c.674C>T	p.Ser225Phe	missense_variant	5/26	1		A2
MYRF	ENST00000675319.1	c.106-1014C>T		intron_variant
TMEM258	ENST00000535042.1	n.649-1713G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 152134 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00174 AC: 307 AN: 176466 Hom.: 4 AF XY: 0.00189 AC XY: 179 AN XY: 94608

Gnomad AFR exome AF: 0.0000977

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00405

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.000553

Gnomad OTH exome AF: 0.000843

GnomAD4 exome AF: 0.000965 AC: 1364 AN: 1413104 Hom.: 11 Cov.: 37 AF XY: 0.00105 AC XY: 734 AN XY: 698482

Gnomad4 AFR exome AF: 0.0000309

Gnomad4 AMR exome AF: 0.0000263

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00472

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.000417

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74414

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000468 Hom.: 0

Bravo AF: 0.000302

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000928 AC: 110

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MYRF-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2019

This variant is classified as 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	0.33
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0090	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.86	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.092
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.77	P;P
Vest4		0.52
MVP		0.11
MPC		0.37
ClinPred		0.13	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs139124174; hg19: chr11-61537958;