Genetic Variant NM_001033.5:c.1659C>T (chr11-4127223-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_001033.5(RRM1):c.1659C>T(p.Tyr553Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,605,048 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 28 hom. )

Consequence

RRM1
NM_001033.5 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0880

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 11-4127223-C-T is Benign according to our data. Variant chr11-4127223-C-T is described in ClinVar as [Benign]. Clinvar id is 719475.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.088 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00199 (2891/1452816) while in subpopulation EAS AF= 0.0221 (875/39646). AF 95% confidence interval is 0.0209. There are 28 homozygotes in gnomad4_exome. There are 1588 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 315 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRM1	NM_001033.5 link	c.1659C>T	p.Tyr553Tyr	synonymous_variant	Exon 14 of 19	ENST00000300738.10	NP_001024.1	P23921
RRM1	NM_001318064.1 link	c.1368C>T	p.Tyr456Tyr	synonymous_variant	Exon 13 of 18		NP_001304993.1	P23921B4E0I8
RRM1	NM_001330193.1 link	c.993C>T	p.Tyr331Tyr	synonymous_variant	Exon 8 of 13		NP_001317122.1	E9PL69
RRM1	NM_001318065.1 link	c.645C>T	p.Tyr215Tyr	synonymous_variant	Exon 8 of 13		NP_001304994.1	P23921B4DXD1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRM1	ENST00000300738.10 link	c.1659C>T	p.Tyr553Tyr	synonymous_variant	Exon 14 of 19	1	NM_001033.5	ENSP00000300738.5		P23921

Frequencies

GnomAD3 genomes

AF:

0.00207

AC:

315

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0139

Gnomad SAS

AF:

0.00973

Gnomad FIN

AF:

0.0123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00380

AC:

907

AN:

238582

Hom.:

AF XY:

0.00386

AC XY:

499

AN XY:

129188

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.0000964

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0161

Gnomad SAS exome

AF:

0.00847

Gnomad FIN exome

AF:

0.0119

Gnomad NFE exome

AF:

0.000948

Gnomad OTH exome

AF:

0.00348

GnomAD4 exome

AF:

0.00199

AC:

2891

AN:

1452816

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

1588

AN XY:

722642

show subpopulations

Gnomad4 AFR exome

AF:

0.000243

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0221

Gnomad4 SAS exome

AF:

0.00738

Gnomad4 FIN exome

AF:

0.0126

Gnomad4 NFE exome

AF:

0.000529

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00207

AC:

315

AN:

152232

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

195

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0139

Gnomad4 SAS

AF:

0.00974

Gnomad4 FIN

AF:

0.0123

Gnomad4 NFE

AF:

0.000764

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000734

Hom.:

Bravo

AF:

0.00121

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 02, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

8.3

DANN

Benign

0.40

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over