11-61766050-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BS1_Supporting BS2

The NM_001127392.3(MYRF):c.227G>A(p.Ser76Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000212 in 1,601,726 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: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: MYRF NM_001127392.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46

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 Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYRF
• BP4: Computational evidence support a benign effect (MetaRNN=0.0125134885).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00021 (32/152238) while in subpopulation NFE AF= 0.000279 (19/67996). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYRF	NM_001127392.3	c.227G>A	p.Ser76Asn	missense_variant	3/27	ENST00000278836.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYRF	ENST00000278836.10	c.227G>A	p.Ser76Asn	missense_variant	3/27	1	NM_001127392.3	P2
MYRF	ENST00000265460.9	c.200G>A	p.Ser67Asn	missense_variant	3/26	1		A2
MYRF	ENST00000537766.1	n.575G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000263 AC: 57 AN: 217110 Hom.: 0 AF XY: 0.000306 AC XY: 37 AN XY: 120748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000339

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.000369

GnomAD4 exome AF: 0.000212 AC: 307 AN: 1449488 Hom.: 0 Cov.: 32 AF XY: 0.000222 AC XY: 160 AN XY: 721000

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000914

Gnomad4 ASJ exome AF: 0.00278

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.0000213

Gnomad4 NFE exome AF: 0.000188

Gnomad4 OTH exome AF: 0.000300

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74414

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000408 Hom.: 0

Bravo AF: 0.000189

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000268 AC: 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

Sep 27, 2022

The c.227G>A (p.S76N) alteration is located in exon 3 (coding exon 3) of the MYRF gene. This alteration results from a G to A substitution at nucleotide position 227, causing the serine (S) at amino acid position 76 to be replaced by an asparagine (N). 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	0.26
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.017	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.93	N;N
REVEL	Benign	0.032
Sift	Benign	0.17	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.65	P;B
Vest4		0.17
MVP		0.25
MPC		0.094
ClinPred		0.064	T
GERP RS		3.5
Varity_R		0.15
gMVP		0.15

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: rs775076363; hg19: chr11-61533522;