11-61770356-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001127392.3(MYRF):c.571C>T(p.Pro191Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000296 in 1,351,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: MYRF NM_001127392.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.83

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYRF
• BP4: Computational evidence support a benign effect (MetaRNN=0.24391079).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYRF	NM_001127392.3	c.571C>T	p.Pro191Ser	missense_variant	5/27	ENST00000278836.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYRF	ENST00000278836.10	c.571C>T	p.Pro191Ser	missense_variant	5/27	1	NM_001127392.3	P2
MYRF	ENST00000265460.9	c.544C>T	p.Pro182Ser	missense_variant	5/26	1		A2
MYRF	ENST00000675319.1	c.106-1144C>T		intron_variant
TMEM258	ENST00000535042.1	n.649-1583G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000296 AC: 4 AN: 1351314 Hom.: 0 Cov.: 29 AF XY: 0.00000449 AC XY: 3 AN XY: 668120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000258

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000192

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.571C>T (p.P191S) alteration is located in exon 5 (coding exon 5) of the MYRF gene. This alteration results from a C to T substitution at nucleotide position 571, causing the proline (P) at amino acid position 191 to be replaced by a serine (S). 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	Benign	0.095
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.038	T;.
Eigen	Benign	0.020
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.093
Sift	Benign	0.26	T;D
Sift4G	Benign	0.22	T;T
Polyphen		0.80	P;P
Vest4		0.43
MutPred		0.40		Gain of phosphorylation at P191 (P = 0.0026);.;
MVP		0.17
MPC		0.17
ClinPred		0.85	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.32

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: chr11-61537828;