chr7-105567208-C-T

Position:

chr7-105567208-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021930.6(RINT1):c.2276C>T(p.Pro759Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00748 in 1,613,198 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 56 hom. )

Consequence

RINT1
NM_021930.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.69

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:

RINT1 (HGNC:):

RINT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006407976).

BP6

Variant 7-105567208-C-T is Benign according to our data. Variant chr7-105567208-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 224921.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 = 0.00524 (798/152330) while in subpopulation NFE AF= 0.00848 (577/68034). AF 95% confidence interval is 0.00791. There are 3 homozygotes in gnomad4. There are 352 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RINT1	NM_021930.6 linkuse as main transcript	c.2276C>T	p.Pro759Leu	missense_variant	15/15	ENST00000257700.7	NP_068749.3	Q6NUQ1
EFCAB10	NM_001355526.2 linkuse as main transcript	c.383+259G>A		intron_variant		ENST00000480514.6	NP_001342455.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RINT1	ENST00000257700.7 linkuse as main transcript	c.2276C>T	p.Pro759Leu	missense_variant	15/15	1	NM_021930.6	ENSP00000257700.2		Q6NUQ1
EFCAB10	ENST00000480514.6 linkuse as main transcript	c.383+259G>A		intron_variant		1	NM_001355526.2	ENSP00000418678.1		A6NFE3

Frequencies

GnomAD3 genomes

AF:

0.00525

AC:

799

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00848

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00545

AC:

1366

AN:

250478

Hom.:

AF XY:

0.00539

AC XY:

730

AN XY:

135336

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00207

Gnomad ASJ exome

AF:

0.0148

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00439

Gnomad FIN exome

AF:

0.00273

Gnomad NFE exome

AF:

0.00786

Gnomad OTH exome

AF:

0.00671

GnomAD4 exome

AF:

0.00772

AC:

11276

AN:

1460868

Hom.:

Cov.:

AF XY:

0.00762

AC XY:

5540

AN XY:

726698

show subpopulations

Gnomad4 AFR exome

AF:

0.00164

Gnomad4 AMR exome

AF:

0.00209

Gnomad4 ASJ exome

AF:

0.0181

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00463

Gnomad4 FIN exome

AF:

0.00275

Gnomad4 NFE exome

AF:

0.00863

Gnomad4 OTH exome

AF:

0.00845

GnomAD4 genome

AF:

0.00524

AC:

798

AN:

152330

Hom.:

Cov.:

AF XY:

0.00472

AC XY:

352

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.00307

Gnomad4 ASJ

AF:

0.0167

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00455

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00848

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00838

Hom.:

Bravo

AF:

0.00482

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00942

AC:

ExAC

AF:

0.00546

AC:

663

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00736

EpiControl

AF:

0.00705

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 02, 2020	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. -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The RINT1 p.Pro418Leu variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs34310648), ClinVar (classified as benign by Invitae), and LOVD 3.0. The variant was identified in control databases in 1493 of 267350 chromosomes (4 homozygous) at a frequency of 0.005584 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: Ashkenazi Jewish in 149 of 9852 chromosomes (freq: 0.01512), European (non-Finnish) in 995 of 117934 chromosomes (freq: 0.008437), Other in 50 of 6678 chromosomes (freq: 0.007487), South Asian in 133 of 30174 chromosomes (freq: 0.004408), European (Finnish) in 64 of 25096 chromosomes (freq: 0.00255), Latino in 69 of 34774 chromosomes (freq: 0.001984) and African in 33 of 23618 chromosomes (freq: 0.001397), but was not observed in the East Asian population. The p.Pro418 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	EFCAB10: BS2; RINT1: BP4, BS2 -

RINT1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as likely 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

0.080

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0092

MetaRNN

Benign

0.0064

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.1

REVEL

Benign

0.052

Sift

Benign

0.030

Sift4G

Uncertain

0.032

Polyphen

0.015

Vest4

0.20

MVP

0.43

MPC

0.20

ClinPred

0.016

GERP RS

5.1

Varity_R

0.098

gMVP

0.30

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