rs148050825

chr7-105547226-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021930.6(RINT1):c.732C>T(p.Ile244=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,614,158 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (10 hom.)
• Consequence: RINT1 NM_021930.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.821

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 7-105547226-C-T is Benign according to our data. Variant chr7-105547226-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-105547226-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.821 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00556 (847/152272) while in subpopulation AFR AF= 0.0195 (810/41548). AF 95% confidence interval is 0.0184. There are 4 homozygotes in gnomad4. There are 409 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RINT1	NM_021930.6	c.732C>T	p.Ile244=	synonymous_variant	6/15	ENST00000257700.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RINT1	ENST00000257700.7	c.732C>T	p.Ile244=	synonymous_variant	6/15	1	NM_021930.6	P1
RINT1	ENST00000467392.5	c.*430C>T		3_prime_UTR_variant, NMD_transcript_variant	6/6	3
RINT1	ENST00000497979.5	c.*337C>T		3_prime_UTR_variant, NMD_transcript_variant	6/15	5

Frequencies

GnomAD3 genomes AF: 0.00557 AC: 847 AN: 152154 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00145 AC: 365 AN: 251460 Hom.: 2 AF XY: 0.00103 AC XY: 140 AN XY: 135898

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000605 AC: 885 AN: 1461886 Hom.: 10 Cov.: 32 AF XY: 0.000543 AC XY: 395 AN XY: 727244

Gnomad4 AFR exome AF: 0.0224

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00556 AC: 847 AN: 152272 Hom.: 4 Cov.: 32 AF XY: 0.00549 AC XY: 409 AN XY: 74464

Gnomad4 AFR AF: 0.0195

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00251 Hom.: 2

Bravo AF: 0.00619

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2020

This alteration is classified as likely 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

RINT1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 2019

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
BayesDel_noAF	Benign	-0.59
Cadd	Benign	2.9
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: -42

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148050825; hg19: chr7-105187673;