11-4106068-T-C

Position:

• chr11-4106068-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001033.5(RRM1):​c.131T>C​(p.Ile44Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RRM1 NM_001033.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRM1	NM_001033.5	c.131T>C	p.Ile44Thr	missense_variant	3/19	ENST00000300738.10	NP_001024.1
RRM1	NM_001318064.1	c.-5-1367T>C		intron_variant			NP_001304993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRM1	ENST00000300738.10	c.131T>C	p.Ile44Thr	missense_variant	3/19	1	NM_001033.5	ENSP00000300738.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2024

The c.131T>C (p.I44T) alteration is located in exon 3 (coding exon 3) of the RRM1 gene. This alteration results from a T to C substitution at nucleotide position 131, causing the isoleucine (I) at amino acid position 44 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.9	M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.052	T
Polyphen		0.11	B
Vest4		0.83
MutPred		0.50		Loss of ubiquitination at K42 (P = 0.051);
MVP		0.57
MPC		2.1
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.80
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-4127298;