11-4106058-ATG-CTA

Variant names:

• chr11-4106058-ATG-CTA
• NM_001033.5:c.121_123delATGinsCTA
• RRM1 p.Met41Leu

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001033.5(RRM1):​c.121_123delATGinsCTA​(p.Met41Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M41V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: RRM1 NM_001033.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.44
• Publications: 0 publications found

Genes affected

RRM1 (HGNC:10451): (ribonucleotide reductase catalytic subunit M1) This gene encodes the large and catalytic subunit of ribonucleotide reductase, an enzyme essential for the conversion of ribonucleotides into deoxyribonucleotides. A pool of available deoxyribonucleotides is important for DNA replication during S phase of the cell cycle as well as multiple DNA repair processes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

RRM1 Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6

  Inheritance: AR, AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, G2P
• progressive external ophthalmoplegia with mitochondrial DNA deletions

  Inheritance: AD, AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033.5. 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
	RRM1	NM_001033.5	MANE Select	c.121_123delATGinsCTA	p.Met41Leu	missense	N/A	NP_001024.1	P23921
	RRM1	NM_001318064.1		c.-5-1377_-5-1375delATGinsCTA		intron	N/A	NP_001304993.1	B4E0I8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRM1	ENST00000300738.10	TSL:1 MANE Select	c.121_123delATGinsCTA	p.Met41Leu	missense	N/A	ENSP00000300738.5	P23921
	RRM1	ENST00000854928.1		c.121_123delATGinsCTA	p.Met41Leu	missense	N/A	ENSP00000524987.1
	RRM1	ENST00000854929.1		c.121_123delATGinsCTA	p.Met41Leu	missense	N/A	ENSP00000524988.1

Frequencies

GnomAD3 genomes Cov.: 30

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

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-4127288;