11-61765977-G-A

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.154G>A(p.Ala52Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,542,138 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: MYRF NM_001127392.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.06

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]

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=0.00487566).
• BP6: Variant 11-61765977-G-A is Benign according to our data. Variant chr11-61765977-G-A is described in ClinVar as [Benign]. Clinvar id is 3043481.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000276 (42/152242) while in subpopulation EAS AF= 0.00736 (38/5162). AF 95% confidence interval is 0.00551. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYRF	NM_001127392.3	c.154G>A	p.Ala52Thr	missense_variant	3/27	ENST00000278836.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYRF	ENST00000278836.10	c.154G>A	p.Ala52Thr	missense_variant	3/27	1	NM_001127392.3	P2
MYRF	ENST00000265460.9	c.127G>A	p.Ala43Thr	missense_variant	3/26	1		A2
MYRF	ENST00000537766.1	n.502G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00734

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000694 AC: 110 AN: 158566 Hom.: 2 AF XY: 0.000601 AC XY: 52 AN XY: 86562

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00763

Gnomad SAS exome AF: 0.0000487

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000246

GnomAD4 exome AF: 0.000211 AC: 293 AN: 1389896 Hom.: 2 Cov.: 32 AF XY: 0.000217 AC XY: 149 AN XY: 685130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000132

Gnomad4 EAS exome AF: 0.00710

Gnomad4 SAS exome AF: 0.0000389

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.000244

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74436

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00736

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000470 Hom.: 1

Bravo AF: 0.000298

ExAC AF: 0.000478 AC: 57

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 10, 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	0.077
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.029	T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.68	T;T
MetaRNN	Benign	0.0049	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.87	N;N
REVEL	Benign	0.015
Sift	Benign	0.43	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.012	B;B
Vest4		0.17
MVP		0.21
MPC		0.10
ClinPred		0.040	T
GERP RS		3.4
Varity_R		0.060
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs202176179; hg19: chr11-61533449;