NM_021930.6:c.1447A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021930.6(RINT1):c.1447A>G(p.Met483Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,610,494 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M483I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RINT1
NM_021930.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.01

Publications

2 publications found

Variant links:

Genes affected

RINT1 (HGNC:21876): (RAD50 interactor 1) This gene encodes a protein first identified for its ability to interact with the RAD50 double strand break repair protein, with the resulting interaction implicated in the regulation of cell cycle progression and telomere length. The encoded protein may also play a role in trafficking of cellular cargo from the endosome to the trans-Golgi network. Mutations in this gene may be associated with breast cancer in human patients. [provided by RefSeq, Oct 2016]

RINT1 Gene-Disease associations (from GenCC):

infantile liver failure syndrome 3
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
infantile liver failure syndrome 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RINT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RINT1	NM_021930.6 link	c.1447A>G	p.Met483Val	missense_variant	Exon 10 of 15	ENST00000257700.7	NP_068749.3	Q6NUQ1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RINT1	ENST00000257700.7 link	c.1447A>G	p.Met483Val	missense_variant	Exon 10 of 15	1	NM_021930.6	ENSP00000257700.2	Q6NUQ1
RINT1	ENST00000474123.1 link	n.451A>G		non_coding_transcript_exon_variant	Exon 3 of 4	2
RINT1	ENST00000497979.5 link	n.*1052A>G		non_coding_transcript_exon_variant	Exon 10 of 15	5		ENSP00000420582.1	F8WDC5
RINT1	ENST00000497979.5 link	n.*1052A>G		3_prime_UTR_variant	Exon 10 of 15	5		ENSP00000420582.1	F8WDC5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458288

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33330

American (AMR)

AF:

0.00

AC:

AN:

44050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26032

East Asian (EAS)

AF:

0.00

AC:

AN:

39590

South Asian (SAS)

AF:

0.00

AC:

AN:

85406

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110504

Other (OTH)

AF:

0.00

AC:

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 19, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M483V variant (also known as c.1447A>G), located in coding exon 10 of the RINT1 gene, results from an A to G substitution at nucleotide position 1447. The methionine at codon 483 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided

Uncertain:1

Oct 27, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine with valine at codon 483 of the RINT1 protein (p.Met483Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature. In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PhyloP100

9.0

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.9

REVEL

Benign

0.25

Sift

Uncertain

0.015

Sift4G

Benign

0.13

Polyphen

0.21

Vest4

0.59

MutPred

0.74

Gain of catalytic residue at M483 (P = 0.1997);

MVP

0.46

MPC

0.25

ClinPred

0.93

GERP RS

5.3

Varity_R

0.34

gMVP

0.50

Mutation Taster

=39/61

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over