chr11-61770350-C-T

Position:

• chr11-61770350-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001127392.3(MYRF):​c.565C>T​(p.Pro189Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYRF NM_001127392.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04

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 Uncertain_significance. Variant got 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29537472).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYRF	NM_001127392.3	c.565C>T	p.Pro189Ser	missense_variant	5/27	ENST00000278836.10	NP_001120864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYRF	ENST00000278836.10	c.565C>T	p.Pro189Ser	missense_variant	5/27	1	NM_001127392.3	ENSP00000278836.4
MYRF	ENST00000265460.9	c.538C>T	p.Pro180Ser	missense_variant	5/26	1		ENSP00000265460.5
MYRF	ENST00000675319.1	c.105-1150C>T		intron_variant				ENSP00000502795.1
TMEM258	ENST00000535042.1	n.649-1577G>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 01, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; 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	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.10
Sift	Uncertain	0.028	D;T
Sift4G	Benign	0.27	T;T
Polyphen		1.0	D;D
Vest4		0.38
MutPred		0.37		Gain of phosphorylation at P189 (P = 0.0025);.;
MVP		0.19
MPC		0.49
ClinPred		0.81	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.28

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.

Other links and lift over

hg19: chr11-61537822;