rs878855071

Positions:

• chr7-105551564-TATCAGTT-TTCA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP3

The NM_021930.6(RINT1):​c.1334-5_1335delinsTCA variant causes a splice acceptor, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RINT1 NM_021930.6 splice_acceptor, coding_sequence, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.83

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05758722 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.8, offset of -1, new splice context is: attgttttgtctgctttcAGctc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RINT1	NM_021930.6	c.1334-5_1335delinsTCA		splice_acceptor_variant, coding_sequence_variant, intron_variant	10/15	ENST00000257700.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RINT1	ENST00000257700.7	c.1334-5_1335delinsTCA		splice_acceptor_variant, coding_sequence_variant, intron_variant	10/15	1	NM_021930.6	P1
RINT1	ENST00000474123.1	n.338-5_339delinsTCA		splice_acceptor_variant, non_coding_transcript_exon_variant, intron_variant	3/4	2
RINT1	ENST00000497979.5	c.*939-5_*940delinsTCA		splice_acceptor_variant, 3_prime_UTR_variant, intron_variant, NMD_transcript_variant	10/15	5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2022

The c.1334-5_1335delATCAGTTinsTCA variant results from a deletion of 7 nucleotides and insertion of three (TCA) nucleotides at positions c.1334-5 to c.1335 and involves the canonical splice acceptor site before coding exon 10 of the RINT1 gene. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site. These models also predict a strong cryptic acceptor site that, if utilized, would result in an in-frame transcript with unknown functional impact. The canonical splice acceptor site is well conserved in available vertebrate species. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 30, 2019

This variant, c.1334-5_1335delinsTCA, is a complex sequence change that results in the deletion of the acceptor splice site in intron 9. It is expected to disrupt RNA splicing and/or create a premature translational stop signal, and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 25050558). It is also known as c.[1334-5delA;1334-1_1335delGTT] in the literature. Experimental studies have shown that this variant alters the mRNA transcript in vitro (PMID: 25050558). It is predicted to result in both a missense change and the deletion of a single amino acid (p.Phe445_Ala446delinsSer), but preserve the integrity of the reading frame. The effect of these changes on protein function have not been determined. In summary, this is a rare, complex variant with uncertain effect on protein function. For these reasons, this change has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs878855071; hg19: chr7-105192012;