rs35531972

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1978C>A(p.Leu660Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,614,154 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts 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. L660F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 8 hom., cov: 33)

Exomes 𝑓: 0.014 ( 178 hom. )

Consequence

RINT1
NM_021930.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.18

Publications

12 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 links:

EFCAB10 (HGNC:34531): (EF-hand calcium binding domain 10) Predicted to enable calcium ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

EFCAB10 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=0.008720905).

BP6

Variant 7-105565368-C-A is Benign according to our data. Variant chr7-105565368-C-A is described in ClinVar as Benign. ClinVar VariationId is 224933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0106 (1611/152318) while in subpopulation NFE AF = 0.0166 (1128/68034). AF 95% confidence interval is 0.0158. There are 8 homozygotes in GnomAd4. There are 758 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RINT1	NM_021930.6 link	c.1978C>A	p.Leu660Ile	missense_variant	Exon 13 of 15	ENST00000257700.7	NP_068749.3
EFCAB10	NM_001355526.2 link	c.*79G>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000480514.6	NP_001342455.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RINT1	ENST00000257700.7 link	c.1978C>A	p.Leu660Ile	missense_variant	Exon 13 of 15	1	NM_021930.6	ENSP00000257700.2
EFCAB10	ENST00000480514.6 link	c.*79G>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_001355526.2	ENSP00000418678.1

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1613

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00273

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00727

Gnomad ASJ

AF:

0.0372

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.00669

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0166

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0117

AC:

2951

AN:

251436

AF XY:

0.0118

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00862

Gnomad ASJ exome

AF:

0.0362

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00679

Gnomad NFE exome

AF:

0.0168

Gnomad OTH exome

AF:

0.0139

GnomAD4 exome

AF:

0.0136

AC:

19881

AN:

1461836

Hom.:

178

Cov.:

AF XY:

0.0134

AC XY:

9738

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00332

AC:

111

AN:

33478

American (AMR)

AF:

0.00798

AC:

357

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0348

AC:

909

AN:

26130

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39694

South Asian (SAS)

AF:

0.00311

AC:

268

AN:

86256

European-Finnish (FIN)

AF:

0.00693

AC:

370

AN:

53416

Middle Eastern (MID)

AF:

0.0257

AC:

148

AN:

5766

European-Non Finnish (NFE)

AF:

0.0152

AC:

16921

AN:

1111980

Other (OTH)

AF:

0.0131

AC:

794

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

1043

2087

3130

4174

5217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

604

1208

1812

2416

3020

<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:

0.0106

AC:

1611

AN:

152318

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

758

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00272

AC:

113

AN:

41574

American (AMR)

AF:

0.00727

AC:

111

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0372

AC:

129

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00228

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00669

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0166

AC:

1128

AN:

68034

Other (OTH)

AF:

0.0109

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

184

275

367

459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0157

Hom.:

Bravo

AF:

0.0108

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0171

AC:

147

ExAC

AF:

0.0115

AC:

1396

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0207

EpiControl

AF:

0.0197

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 30, 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. -

Infantile liver failure syndrome 3

Benign:1

Aug 07, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

RINT1-related disorder

Benign:1

Feb 19, 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

0.14

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0087

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

3.2

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.66

REVEL

Benign

0.16

Sift

Benign

0.33

Sift4G

Benign

0.24

Polyphen

1.0

Vest4

0.23

MPC

0.76

ClinPred

0.011

GERP RS

5.5

Varity_R

0.26

gMVP

0.17

Mutation Taster

=95/5

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over