11-4107509-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001033.5(RRM1):c.361T>C(p.Leu121=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,613,050 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (31 hom.)
• Consequence: RRM1 NM_001033.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.16

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 11-4107509-T-C is Benign according to our data. Variant chr11-4107509-T-C is described in ClinVar as [Benign]. Clinvar id is 731616.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0102 (1548/152328) while in subpopulation AFR AF= 0.0322 (1337/41572). AF 95% confidence interval is 0.0307. There are 15 homozygotes in gnomad4. There are 759 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1545 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRM1	NM_001033.5	c.361T>C	p.Leu121=	synonymous_variant	4/19	ENST00000300738.10
RRM1	NM_001318064.1	c.70T>C	p.Leu24=	synonymous_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRM1	ENST00000300738.10	c.361T>C	p.Leu121=	synonymous_variant	4/19	1	NM_001033.5	P1

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1545 AN: 152210 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00372 AC: 934 AN: 251368 Hom.: 8 AF XY: 0.00305 AC XY: 415 AN XY: 135862

Gnomad AFR exome AF: 0.0321

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00176 AC: 2573 AN: 1460722 Hom.: 31 Cov.: 29 AF XY: 0.00157 AC XY: 1140 AN XY: 726740

Gnomad4 AFR exome AF: 0.0343

Gnomad4 AMR exome AF: 0.00340

Gnomad4 ASJ exome AF: 0.0228

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000360

Gnomad4 OTH exome AF: 0.00396

GnomAD4 genome AF: 0.0102 AC: 1548 AN: 152328 Hom.: 15 Cov.: 33 AF XY: 0.0102 AC XY: 759 AN XY: 74504

Gnomad4 AFR AF: 0.0322

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00637 Hom.: 7

Bravo AF: 0.0118

Asia WGS AF: 0.00202 AC: 8 AN: 3476

EpiCase AF: 0.00120

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	6.6
Dann	Benign	0.76
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: rs2228121; hg19: chr11-4128739;