rs779858495

Variant names:

• chr11-4102062-A-G
• rs779858495
• NM_001033.5:c.89A>G

Variant summary

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

The NM_001033.5(RRM1):​c.89A>G​(p.Asn30Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000699 in 1,430,718 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: RRM1 NM_001033.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.88
• 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

  Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics
• progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6

  Inheritance: AR, AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.89A>G	p.Asn30Ser	missense	Exon 2 of 19	NP_001024.1	P23921
	RRM1	NM_001318064.1		c.-25A>G		5_prime_UTR	Exon 2 of 18	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.89A>G	p.Asn30Ser	missense	Exon 2 of 19	ENSP00000300738.5	P23921
	RRM1	ENST00000854928.1		c.89A>G	p.Asn30Ser	missense	Exon 2 of 19	ENSP00000524987.1
	RRM1	ENST00000854929.1		c.89A>G	p.Asn30Ser	missense	Exon 2 of 18	ENSP00000524988.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000162 AC: 4 AN: 247288 AF XY: 0.0000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000699 AC: 10 AN: 1430718 Hom.: 0 Cov.: 24 AF XY: 0.00000701 AC XY: 5 AN XY: 713560

African (AFR) AF: 0.00 AC: 0 AN: 32690

American (AMR) AF: 0.0000686 AC: 3 AN: 43756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25876

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39494

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000368 AC: 4 AN: 1086076

Other (OTH) AF: 0.0000168 AC: 1 AN: 59378

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		8.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.13
Sift	Benign	0.23	T
Sift4G	Benign	0.25	T
Polyphen		0.015	B
Vest4		0.79
MutPred		0.43		Gain of catalytic residue at N30 (P = 0.0609)
MVP		0.65
MPC		0.70
ClinPred		0.27	T
GERP RS		6.0
Varity_R		0.25
gMVP		0.72
Mutation Taster		=62/38	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: rs779858495; hg19: chr11-4123292;