NM_021930.6:c.1025T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021930.6(RINT1):c.1025T>C(p.Met342Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000987 in 1,613,208 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M342I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00072 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 31 hom. )

Consequence

RINT1
NM_021930.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.55

Publications

5 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012312591).

BP6

Variant 7-105550083-T-C is Benign according to our data. Variant chr7-105550083-T-C is described in ClinVar as Benign. ClinVar VariationId is 224922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000722 (110/152346) while in subpopulation SAS AF = 0.0128 (62/4828). AF 95% confidence interval is 0.0103. There are 1 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 31 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RINT1	NM_021930.6 link	c.1025T>C	p.Met342Thr	missense_variant	Exon 8 of 15	ENST00000257700.7	NP_068749.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RINT1	ENST00000257700.7 link	c.1025T>C	p.Met342Thr	missense_variant	Exon 8 of 15	1	NM_021930.6	ENSP00000257700.2
RINT1	ENST00000474123.1 link	n.29T>C		non_coding_transcript_exon_variant	Exon 1 of 4	2
RINT1	ENST00000497979.5 link	n.*630T>C		non_coding_transcript_exon_variant	Exon 8 of 15	5		ENSP00000420582.1
RINT1	ENST00000497979.5 link	n.*630T>C		3_prime_UTR_variant	Exon 8 of 15	5		ENSP00000420582.1

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0128

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00185

AC:

465

AN:

250982

AF XY:

0.00248

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00101

AC:

1482

AN:

1460862

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

1030

AN XY:

726678

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33442

American (AMR)

AF:

0.000201

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00329

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.0130

AC:

1116

AN:

86116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000144

AC:

160

AN:

1111342

Other (OTH)

AF:

0.00131

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

139

208

278

347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000722

AC:

110

AN:

152346

Hom.:

Cov.:

AF XY:

0.000872

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41592

American (AMR)

AF:

0.000327

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.0128

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000641

Hom.:

Bravo

AF:

0.000423

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00203

AC:

246

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RINT1: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jul 02, 2020

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The RINT1 p.M1? variant was not identified in the literature but was identified in dbSNP (ID: rs140651827) and ClinVar (classified as benign by Invitae).Â¬â€ The variant was identified in control databases in 475 of 282394 chromosomes (13 homozygous) at a frequency of 0.001682, and was observed at the highest frequency in the South Asian population in 385 of 30490 chromosomes (12 homozygous) (freq: 0.01263) (Genome Aggregation Database March 6, 2019, v2.1.1).Â¬â€ The p.M1? variant results in the loss of the initiation codon which is predicted to lead to an absent protein and loss of function; however, the role of loss of function variants of the RINT1 gene in disease is currently not well-established.Â¬â€ The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

RINT1-related disorder

Benign:1

Feb 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.068

Eigen

Benign

-0.11

Eigen_PC

Benign

0.10

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

5.6

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.63

REVEL

Benign

0.10

Sift

Benign

1.0

Sift4G

Uncertain

0.029

Polyphen

0.0030

Vest4

0.55

MVP

0.36

MPC

0.22

ClinPred

0.025

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.097

gMVP

0.32

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over