11-61766173-GCACCGGGCCCCCCATC-T

Variant names:

• chr11-61766173-GCACCGGGCCCCCCATC-T
• rs1565286228
• NM_001127392.3:c.350_366delGCACCGGGCCCCCCATCinsT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001127392.3(MYRF):​c.350_366delGCACCGGGCCCCCCATCinsT​(p.Gly117ValfsTer31) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYRF NM_001127392.3 frameshift, missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.58
• Publications: 3 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-61766173-GCACCGGGCCCCCCATC-T is Pathogenic according to our data. Variant chr11-61766173-GCACCGGGCCCCCCATC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 635276.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.350_366delGCACCGGGCCCCCCATCinsT	p.Gly117ValfsTer31	frameshift missense	Exon 3 of 27	NP_001120864.1	Q9Y2G1-1
	MYRF	NM_013279.4		c.323_339delGCACCGGGCCCCCCATCinsT	p.Gly108ValfsTer31	frameshift 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.350_366delGCACCGGGCCCCCCATCinsT	p.Gly117ValfsTer31	frameshift missense	Exon 3 of 27	ENSP00000278836.4	Q9Y2G1-1
	MYRF	ENST00000265460.9	TSL:1	c.323_339delGCACCGGGCCCCCCATCinsT	p.Gly108ValfsTer31	frameshift missense	Exon 3 of 26	ENSP00000265460.5	Q9Y2G1-2
	MYRF	ENST00000856811.1		c.350_366delGCACCGGGCCCCCCATCinsT	p.Gly117ValfsTer31	frameshift missense	Exon 3 of 27	ENSP00000526870.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiac-urogenital syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1565286228; hg19: chr11-61533645;