11-61766208-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001127392.3(MYRF):c.385C>T(p.Pro129Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYRF NM_001127392.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

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]

ACMG classification

Verdict is Likely_benign. 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=0.037452966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYRF	NM_001127392.3	c.385C>T	p.Pro129Ser	missense_variant	3/27	ENST00000278836.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYRF	ENST00000278836.10	c.385C>T	p.Pro129Ser	missense_variant	3/27	1	NM_001127392.3	P2
MYRF	ENST00000265460.9	c.358C>T	p.Pro120Ser	missense_variant	3/26	1		A2
MYRF	ENST00000675319.1	c.94C>T	p.Pro32Ser	missense_variant	1/23
MYRF	ENST00000537766.1	n.733C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455362 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724274

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Encephalitis/encephalopathy, mild, with reversible myelin vacuolization;C4748946:Cardiac-urogenital syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Aug 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.013	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.95	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.088
Sift	Benign	0.64	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.022	B;B
Vest4		0.11
MutPred		0.19		Loss of catalytic residue at P129 (P = 0.0123);.;
MVP		0.068
MPC		0.11
ClinPred		0.36	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.11

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

LitVar

Other links and lift over

dbSNP: rs1391704383; hg19: chr11-61533680; COSMIC: COSV104546558; COSMIC: COSV104546558;