chr11-61769301-A-G

Variant names:

• chr11-61769301-A-G
• NM_001127392.3:c.440A>G

Variant summary

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

The NM_001127392.3(MYRF):​c.440A>G​(p.Tyr147Cys) variant causes a missense change. 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: 33)
• Consequence: MYRF NM_001127392.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.74

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 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=0.40258673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYRF	NM_001127392.3	c.440A>G	p.Tyr147Cys	missense_variant	Exon 4 of 27	ENST00000278836.10	NP_001120864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYRF	ENST00000278836.10	c.440A>G	p.Tyr147Cys	missense_variant	Exon 4 of 27	1	NM_001127392.3	ENSP00000278836.4
MYRF	ENST00000265460.9	c.413A>G	p.Tyr138Cys	missense_variant	Exon 4 of 26	1		ENSP00000265460.5
MYRF	ENST00000675319.1	c.105-2199A>G		intron_variant	Intron 1 of 22			ENSP00000502795.1
TMEM258	ENST00000535042.1	n.649-528T>C		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.440A>G (p.Y147C) alteration is located in exon 4 (coding exon 4) of the MYRF gene. This alteration results from a A to G substitution at nucleotide position 440, causing the tyrosine (Y) at amino acid position 147 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-0.73	T
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.44
Sift	Benign	0.066	T;T
Sift4G	Benign	0.15	T;T
Polyphen		1.0	D;D
Vest4		0.49
MutPred		0.34		Loss of phosphorylation at Y147 (P = 0.0053);.;
MVP		0.28
MPC		0.58
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.49
gMVP		0.45

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: chr11-61536773;