NM_001127392.3:c.227G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBS1_SupportingBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.46

Variant links:

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]

MYRF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in the MYRF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 3.2927 (above the threshold of 3.09). Trascript score misZ: 3.5469 (above the threshold of 3.09). GenCC associations: The gene is linked to encephalitis/encephalopathy, mild, with reversible myelin vacuolization, cardiac-urogenital syndrome.

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 GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYRF	NM_001127392.3 link	c.227G>A	p.Ser76Asn	missense_variant	Exon 3 of 27	ENST00000278836.10	NP_001120864.1	Q9Y2G1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYRF	ENST00000278836.10 link	c.227G>A	p.Ser76Asn	missense_variant	Exon 3 of 27	1	NM_001127392.3	ENSP00000278836.4	Q9Y2G1-1
MYRF	ENST00000265460.9 link	c.200G>A	p.Ser67Asn	missense_variant	Exon 3 of 26	1		ENSP00000265460.5	Q9Y2G1-2
MYRF	ENST00000537766.1 link	n.575G>A		non_coding_transcript_exon_variant	Exon 2 of 2	3
MYRF	ENST00000675319.1 link	c.-68G>A		upstream_gene_variant				ENSP00000502795.1	A0A6Q8PHM1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

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:

AN:

217110

Hom.:

AF XY:

0.000306

AC XY:

AN XY:

120748

show subpopulations

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.:

Cov.:

AF XY:

0.000222

AC XY:

160

AN XY:

721000

show subpopulations

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:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74414

show subpopulations

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.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000268

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.017

T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.078

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.56

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over