chr11-61766173-GCACCGGGCCCCCCATC-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP2 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. 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 11-61766173-GCACCGGGCCCCCCATC-T is Pathogenic according to our data. Variant chr11-61766173-GCACCGGGCCCCCCATC-T is described in ClinVar as [Pathogenic]. Clinvar id is 635276.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYRF	NM_001127392.3	c.350_366delGCACCGGGCCCCCCATCinsT	p.Gly117ValfsTer31	frameshift_variant, missense_variant	Exon 3 of 27	ENST00000278836.10	NP_001120864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYRF	ENST00000278836.10	c.350_366delGCACCGGGCCCCCCATCinsT	p.Gly117ValfsTer31	frameshift_variant, missense_variant	Exon 3 of 27	1	NM_001127392.3	ENSP00000278836.4
MYRF	ENST00000265460.9	c.323_339delGCACCGGGCCCCCCATCinsT	p.Gly108ValfsTer31	frameshift_variant, missense_variant	Exon 3 of 26	1		ENSP00000265460.5
MYRF	ENST00000675319.1	c.56_72delGCACCGGGCCCCCCATCinsT	p.Gly19LysfsTer916	frameshift_variant, missense_variant	Exon 1 of 23			ENSP00000502795.1
MYRF	ENST00000537766.1	n.698_714delGCACCGGGCCCCCCATCinsT		non_coding_transcript_exon_variant	Exon 2 of 2	3

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cardiac-urogenital syndrome Pathogenic:1

Apr 06, 2019

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1565286228; hg19: chr11-61533645;