chr7-105551565-ATCAGTT-TCA

Variant names:

• chr7-105551565-ATCAGTT-TCA
• rs878855071
• NM_021930.6:c.1334-5_1335delATCAGTTinsTCA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_021930.6(RINT1):​c.1334-5_1335delATCAGTTinsTCA​(p.Phe445fs) variant causes a frameshift, splice acceptor, splice region, synonymous, 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RINT1 NM_021930.6 frameshift, splice_acceptor, splice_region, synonymous, 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 Pathogenic. Variant got 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RINT1	NM_021930.6	c.1334-5_1335delATCAGTTinsTCA	p.Phe445fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, synonymous_variant, intron_variant	Exon 10 of 15	ENST00000257700.7	NP_068749.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RINT1	ENST00000257700.7	c.1334-5_1335delATCAGTTinsTCA	p.Phe445fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, synonymous_variant, intron_variant	Exon 10 of 15	1	NM_021930.6	ENSP00000257700.2
RINT1	ENST00000497979.5	n.*939-5_*940delATCAGTTinsTCA		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 15	5		ENSP00000420582.1
RINT1	ENST00000474123.1	n.338-5_339delATCAGTTinsTCA		splice_acceptor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	Exon 3 of 4	2
RINT1	ENST00000497979.5	n.*939-5_*940delATCAGTTinsTCA		splice_acceptor_variant, splice_region_variant, 3_prime_UTR_variant, intron_variant	Exon 10 of 15	5		ENSP00000420582.1

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

Feb 23, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 30, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;