rs869312981

Positions:

• chr7-105555223-ATGT-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_021930.6(RINT1):​c.1671_1671+2delTGT​(p.Phe558fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,459,656 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: RINT1 NM_021930.6 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.39

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-105555223-ATGT-A is Pathogenic according to our data. Variant chr7-105555223-ATGT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224920.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RINT1	NM_021930.6	c.1671_1671+2delTGT	p.Phe558fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	11/15	ENST00000257700.7	NP_068749.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RINT1	ENST00000257700.7	c.1671_1671+2delTGT	p.Phe558fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	11/15	1	NM_021930.6	ENSP00000257700.2
RINT1	ENST00000474123.1	n.675_677delTGT		non_coding_transcript_exon_variant	4/4	2
RINT1	ENST00000497979.5	n.*1276_*1276+2delTGT		splice_region_variant, non_coding_transcript_exon_variant	11/15	5		ENSP00000420582.1
RINT1	ENST00000497979.5	n.*1276_*1276+2delTGT		splice_donor_variant, 3_prime_UTR_variant, intron_variant	11/15	5		ENSP00000420582.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000360 AC: 9 AN: 249898 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1459656 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 726160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jan 09, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2020	This sequence change deletes 3 nucleotides from exon 11 of the RINT1 mRNA (c.1671_1671+2delTGT), corresponding to the last nucleotide of exon 11 and the donor splice site in intron 11. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in RINT1 cause disease. Nucleotide substitutions at the last nucleotide of the exon and donor splice site in the intron are relatively common causes of aberrant splicing (PMID: 17576681). However, according to multiple splice site algorithms this variant does not result in a significant splicing alteration. An adjacent GT dinucleotide (c.1669_1670) has the potential to serve as a new donor splice site that, if used, would result in an in-frame deletion of Val557. There is also the possibility that this alternate site is not used, which may result in aberrant splicing. Neither of these predictions has been confirmed by published functional studies. This variant has not been reported in the literature in individuals with RINT1-related disease. ClinVar contains an entry for this variant (Variation ID: 224920). This variant is present in population databases (rs774457611, ExAC 0.01%). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2021

The c.1671_1671+2delTGT variant results from a deletion of three nucleotides between positions 1671 and 1671+2 and involves the canonical splice donor site after coding exon 11 of the RINT1 gene. The canonical splice donor site is well conserved through mammals. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, the gene-disease association for RINT1 is limited. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs869312981; hg19: chr7-105195670;