Genetic Variant NM_001127392.3:c.485C>A (chr11-61770270-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_001127392.3(MYRF):c.485C>A(p.Thr162Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000481 in 1,456,518 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MYRF
NM_001127392.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.70

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:

TMEM258 (HGNC:1164): (transmembrane protein 258) Involved in protein N-linked glycosylation. Located in endoplasmic reticulum. Part of oligosaccharyltransferase I complex. [provided by Alliance of Genome Resources, Apr 2022]

TMEM258 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 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.

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYRF	NM_001127392.3 link	c.485C>A	p.Thr162Asn	missense_variant	Exon 5 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.485C>A	p.Thr162Asn	missense_variant	Exon 5 of 27	1	NM_001127392.3	ENSP00000278836.4	Q9Y2G1-1
MYRF	ENST00000265460.9 link	c.458C>A	p.Thr153Asn	missense_variant	Exon 5 of 26	1		ENSP00000265460.5	Q9Y2G1-2
MYRF	ENST00000675319.1 link	c.105-1230C>A		intron_variant	Intron 1 of 22			ENSP00000502795.1	A0A6Q8PHM1
TMEM258	ENST00000535042.1 link	n.649-1497G>T		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000417

AC:

AN:

239944

Hom.:

AF XY:

0.00000764

AC XY:

AN XY:

130834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000333

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000481

AC:

AN:

1456518

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724388

show subpopulations

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:

0.0000350

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.077

T;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Benign

-0.98

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.14

Sift

Benign

0.055

T;D

Sift4G

Benign

0.51

T;T

Polyphen

1.0

D;D

Vest4

0.72

MutPred

0.19

Gain of sheet (P = 0.0344);.;

MVP

0.18

MPC

0.55

ClinPred

0.79

GERP RS

3.9

Varity_R

0.37

gMVP

0.48

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over