11-61766122-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001127392.3(MYRF):c.299A>T(p.Asn100Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYRF NM_001127392.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.30

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYRF
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYRF	NM_001127392.3	c.299A>T	p.Asn100Ile	missense_variant	3/27	ENST00000278836.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYRF	ENST00000278836.10	c.299A>T	p.Asn100Ile	missense_variant	3/27	1	NM_001127392.3	P2
MYRF	ENST00000265460.9	c.272A>T	p.Asn91Ile	missense_variant	3/26	1		A2
MYRF	ENST00000675319.1	c.8A>T	p.Asn3Ile	missense_variant	1/23
MYRF	ENST00000537766.1	n.647A>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457826 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725374

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Mar 22, 2023

The c.299A>T (p.N100I) alteration is located in exon 3 (coding exon 3) of the MYRF gene. This alteration results from a A to T substitution at nucleotide position 299, causing the asparagine (N) at amino acid position 100 to be replaced by an isoleucine (I). 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	0.44
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Benign	0.23
Sift	Benign	0.038	D;D
Sift4G	Uncertain	0.033	D;T
Polyphen		1.0	D;D
Vest4		0.86
MutPred		0.22		Gain of sheet (P = 0.0125);.;
MVP		0.27
MPC		0.58
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.54
gMVP		0.37

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: rs2066054571; hg19: chr11-61533594;