rs174535

Positions:

• chr11-61783884-T-A
• chr11-61783884-T-C
• chr11-61783884-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001127392.3(MYRF):​c.3153T>A​(p.Ser1051Arg) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYRF NM_001127392.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41

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 5 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). GenCC has associacion of gene with encephalitis/encephalopathy, mild, with reversible myelin vacuolization, cardiac-urogenital syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYRF	NM_001127392.3	c.3153T>A	p.Ser1051Arg	missense_variant	24/27	ENST00000278836.10	NP_001120864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYRF	ENST00000278836.10	c.3153T>A	p.Ser1051Arg	missense_variant	24/27	1	NM_001127392.3	ENSP00000278836	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.85	T;D;T
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	0.0018	P;P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D;T;D
Sift4G	Benign	0.088	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.73
MutPred		0.24		Loss of glycosylation at S1051 (P = 0.0483);.;.;
MVP		0.55
MPC		1.1
ClinPred		0.97	D
GERP RS		1.3
Varity_R		0.56
gMVP		0.98

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: rs174535; hg19: chr11-61551356;