NM_001127392.3:c.313A>G

Variant names:

• chr11-61766136-A-G
• rs2135748075
• NM_001127392.3:c.313A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001127392.3(MYRF):​c.313A>G​(p.Asn105Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,388 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYRF NM_001127392.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.27
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• cardiac-urogenital syndrome

  Inheritance: AD Classification: STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hyperopia

  Inheritance: AD Classification: STRONG Submitted by: G2P
• encephalitis/encephalopathy, mild, with reversible myelin vacuolization

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-61766136-A-G is Pathogenic according to our data. Variant chr11-61766136-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1202589.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127392.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYRF	NM_001127392.3	MANE Select	c.313A>G	p.Asn105Asp	missense	Exon 3 of 27	NP_001120864.1	Q9Y2G1-1
	MYRF	NM_013279.4		c.286A>G	p.Asn96Asp	missense	Exon 3 of 26	NP_037411.1	Q9Y2G1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYRF	ENST00000278836.10	TSL:1 MANE Select	c.313A>G	p.Asn105Asp	missense	Exon 3 of 27	ENSP00000278836.4	Q9Y2G1-1
	MYRF	ENST00000265460.9	TSL:1	c.286A>G	p.Asn96Asp	missense	Exon 3 of 26	ENSP00000265460.5	Q9Y2G1-2
	MYRF	ENST00000856811.1		c.313A>G	p.Asn105Asp	missense	Exon 3 of 27	ENSP00000526870.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458388 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725620

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111310

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Disorder of sexual differentiation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.93	T
PhyloP100		6.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.11
Sift	Benign	0.075	T
Sift4G	Benign	0.089	T
Polyphen		1.0	D
Vest4		0.67
MutPred		0.25		Loss of stability (P = 0.3716)
MVP		0.38
MPC		0.55
ClinPred		0.97	D
GERP RS		4.4
PromoterAI		-0.0052	Neutral
Varity_R		0.29
gMVP		0.31
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs2135748075; hg19: chr11-61533608;