chr7-105565270-TTTCCAGATGG-T

Position:

• chr7-105565270-TTTCCAGATGG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Moderate PM2 PP3 PP5_Moderate

The NM_021930.6(RINT1):​c.1887-4_1892del variant causes a splice acceptor, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,409,462 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RINT1 NM_021930.6 splice_acceptor, coding_sequence, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.78

Genes affected

EFCAB10 (HGNC:34531): (EF-hand calcium binding domain 10) Predicted to enable calcium ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.07566204 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.6, offset of 12, new splice context is: ttttgtccttgccatctcAGtca. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift 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
• PP5: Variant 7-105565270-TTTCCAGATGG-T is Pathogenic according to our data. Variant chr7-105565270-TTTCCAGATGG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1930427.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFCAB10	NM_001355526.2	c.*167_*176del		3_prime_UTR_variant	5/5	ENST00000480514.6
RINT1	NM_021930.6	c.1887-4_1892del		splice_acceptor_variant, coding_sequence_variant, intron_variant	13/15	ENST00000257700.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFCAB10	ENST00000480514.6	c.*167_*176del		3_prime_UTR_variant	5/5	1	NM_001355526.2	A2
RINT1	ENST00000257700.7	c.1887-4_1892del		splice_acceptor_variant, coding_sequence_variant, intron_variant	13/15	1	NM_021930.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1409462 Hom.: 0 AF XY: 0.00000144 AC XY: 1 AN XY: 696370

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: 9.20e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 01, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1930427). This variant has not been reported in the literature in individuals affected with RINT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 13 (c.1887-4_1892del) of the RINT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RINT1 are known to be pathogenic (PMID: 31204009). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-105205717;