11-4138227-A-G

Position:

• chr11-4138227-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_001033.5(RRM1):​c.2223A>G​(p.Thr741=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.503 in 1,582,966 control chromosomes in the GnomAD database, including 208,637 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.41 (14553 hom., cov: 29)
  • Exomes 𝑓: 0.51 (194084 hom.)
• Consequence: RRM1 NM_001033.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.447

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-AS1 (HGNC:40512): (RRM1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP7: Synonymous conserved (PhyloP=-0.447 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRM1	NM_001033.5	c.2223A>G	p.Thr741=	synonymous_variant	19/19	ENST00000300738.10
RRM1	NM_001318064.1	c.1932A>G	p.Thr644=	synonymous_variant	18/18
RRM1	NM_001330193.1	c.1557A>G	p.Thr519=	synonymous_variant	13/13
RRM1	NM_001318065.1	c.1209A>G	p.Thr403=	synonymous_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRM1	ENST00000300738.10	c.2223A>G	p.Thr741=	synonymous_variant	19/19	1	NM_001033.5	P1
RRM1-AS1	ENST00000529323.1	n.31T>C		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61833 AN: 151724 Hom.: 14561 Cov.: 29

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.515

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.442

GnomAD3 exomes AF: 0.461 AC: 113624 AN: 246406 Hom.: 27694 AF XY: 0.464 AC XY: 61932 AN XY: 133416

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.463

Gnomad ASJ exome AF: 0.504

Gnomad EAS exome AF: 0.374

Gnomad SAS exome AF: 0.367

Gnomad FIN exome AF: 0.467

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.489

GnomAD4 exome AF: 0.513 AC: 733925 AN: 1431124 Hom.: 194084 Cov.: 26 AF XY: 0.510 AC XY: 363856 AN XY: 713600

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.458

Gnomad4 ASJ exome AF: 0.503

Gnomad4 EAS exome AF: 0.423

Gnomad4 SAS exome AF: 0.367

Gnomad4 FIN exome AF: 0.470

Gnomad4 NFE exome AF: 0.546

Gnomad4 OTH exome AF: 0.478

GnomAD4 genome AF: 0.407 AC: 61820 AN: 151842 Hom.: 14553 Cov.: 29 AF XY: 0.402 AC XY: 29788 AN XY: 74180

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.453

Gnomad4 ASJ AF: 0.515

Gnomad4 EAS AF: 0.384

Gnomad4 SAS AF: 0.376

Gnomad4 FIN AF: 0.455

Gnomad4 NFE AF: 0.537

Gnomad4 OTH AF: 0.438

Alfa AF: 0.478 Hom.: 10717

Bravo AF: 0.400

Asia WGS AF: 0.346 AC: 1204 AN: 3478

EpiCase AF: 0.540

EpiControl AF: 0.544

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs9937; hg19: chr11-4159457; COSMIC: COSV56163380;