11-4127245-G-T

Variant names:

• chr11-4127245-G-T
• rs781083706
• NM_001033.5:c.1681G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001033.5(RRM1):​c.1681G>T​(p.Val561Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,656 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V561L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RRM1 NM_001033.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.53
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1681G>T	p.Val561Phe	missense	Exon 14 of 19	NP_001024.1	P23921
	RRM1	NM_001318064.1		c.1390G>T	p.Val464Phe	missense	Exon 13 of 18	NP_001304993.1	B4E0I8
	RRM1	NM_001330193.1		c.1015G>T	p.Val339Phe	missense	Exon 8 of 13	NP_001317122.1	E9PL69

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRM1	ENST00000300738.10	TSL:1 MANE Select	c.1681G>T	p.Val561Phe	missense	Exon 14 of 19	ENSP00000300738.5	P23921
	RRM1	ENST00000854928.1		c.1612G>T	p.Val538Phe	missense	Exon 14 of 19	ENSP00000524987.1
	RRM1	ENST00000534285.5	TSL:5	c.1015G>T	p.Val339Phe	missense	Exon 8 of 13	ENSP00000431464.1	E9PL69

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434656 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 712902

African (AFR) AF: 0.00 AC: 0 AN: 32228

American (AMR) AF: 0.00 AC: 0 AN: 38598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24148

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.00 AC: 0 AN: 81168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102262

Other (OTH) AF: 0.00 AC: 0 AN: 59110

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.29
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.70	T
Polyphen		0.76	P
Vest4		0.80
MutPred		0.56		Loss of ubiquitination at K563 (P = 0.0777)
MVP		0.56
MPC		1.7
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.86
gMVP		0.96
Mutation Taster		=4/96	disease causing

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: rs781083706; hg19: chr11-4148475;