rs35961194

Positions:

• chr7-105551610-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_021930.6(RINT1):​c.1374T>C​(p.Ala458Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,609,958 control chromosomes in the GnomAD database, including 436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (32 hom., cov: 32)
  • Exomes 𝑓: 0.017 (404 hom.)
• Consequence: RINT1 NM_021930.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.31

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 7-105551610-T-C is Benign according to our data. Variant chr7-105551610-T-C is described in ClinVar as [Benign]. Clinvar id is 224930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-105551610-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RINT1	NM_021930.6	c.1374T>C	p.Ala458Ala	synonymous_variant	10/15	ENST00000257700.7	NP_068749.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RINT1	ENST00000257700.7	c.1374T>C	p.Ala458Ala	synonymous_variant	10/15	1	NM_021930.6	ENSP00000257700.2
RINT1	ENST00000474123.1	n.378T>C		non_coding_transcript_exon_variant	3/4	2
RINT1	ENST00000497979.5	n.*979T>C		non_coding_transcript_exon_variant	10/15	5		ENSP00000420582.1
RINT1	ENST00000497979.5	n.*979T>C		3_prime_UTR_variant	10/15	5		ENSP00000420582.1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2146 AN: 152210 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00369

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0411

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0239 AC: 5945 AN: 248530 Hom.: 238 AF XY: 0.0201 AC XY: 2706 AN XY: 134320

Gnomad AFR exome AF: 0.00315

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.00339

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00348

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0216

GnomAD4 exome AF: 0.0169 AC: 24638 AN: 1457630 Hom.: 404 Cov.: 30 AF XY: 0.0161 AC XY: 11671 AN XY: 725088

Gnomad4 AFR exome AF: 0.00309

Gnomad4 AMR exome AF: 0.0990

Gnomad4 ASJ exome AF: 0.00461

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00318

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.0166

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.0141 AC: 2148 AN: 152328 Hom.: 32 Cov.: 32 AF XY: 0.0132 AC XY: 987 AN XY: 74494

Gnomad4 AFR AF: 0.00368

Gnomad4 AMR AF: 0.0411

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00951

Gnomad4 NFE AF: 0.0175

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0151 Hom.: 10

Bravo AF: 0.0195

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 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. -

RINT1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 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	-0.44
CADD	Benign	12
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs35961194; hg19: chr7-105192057;