11-61766146-G-A

Position:

chr11-61766146-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2

The NM_001127392.3(MYRF):c.323G>A(p.Gly108Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,611,422 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: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

MYRF
NM_001127392.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.17

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:

MYRF (HGNC:):

MYRF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYRF. . Gene score misZ 3.2927 (greater than the threshold 3.09). Trascript score misZ 3.5469 (greater than threshold 3.09). GenCC has associacion of gene with encephalitis/encephalopathy, mild, with reversible myelin vacuolization, cardiac-urogenital syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.23184079).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000526 (8/152218) while in subpopulation AMR AF= 0.000458 (7/15294). AF 95% confidence interval is 0.000215. There are 0 homozygotes in gnomad4. There are 6 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 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYRF	NM_001127392.3 linkuse as main transcript	c.323G>A	p.Gly108Asp	missense_variant	3/27	ENST00000278836.10	NP_001120864.1	Q9Y2G1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYRF	ENST00000278836.10 linkuse as main transcript	c.323G>A	p.Gly108Asp	missense_variant	3/27	1	NM_001127392.3	ENSP00000278836.4	Q9Y2G1-1
MYRF	ENST00000265460.9 linkuse as main transcript	c.296G>A	p.Gly99Asp	missense_variant	3/26	1		ENSP00000265460.5	Q9Y2G1-2
MYRF	ENST00000675319.1 linkuse as main transcript	c.29G>A	p.Gly10Asp	missense_variant	1/23			ENSP00000502795.1	A0A6Q8PHM1
MYRF	ENST00000537766.1 linkuse as main transcript	n.671G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000337

AC:

AN:

237156

Hom.:

AF XY:

0.0000459

AC XY:

AN XY:

130694

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000875

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000481

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1459204

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726000

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000250

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2022

The c.323G>A (p.G108D) 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 323, causing the glycine (G) at amino acid position 108 to be replaced by an aspartic acid (D). 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

0.23

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

T;.

Eigen

Benign

-0.076

Eigen_PC

Benign

-0.0063

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.0079

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.065

Sift

Uncertain

0.017

D;D

Sift4G

Benign

0.16

T;T

Polyphen

0.89

P;P

Vest4

0.54

MutPred

0.18

Gain of solvent accessibility (P = 0.1014);.;

MVP

0.17

MPC

0.20

ClinPred

0.14

GERP RS

4.4

Varity_R

0.14

gMVP

0.28

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