rs113947297

chr7-105548549-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_021930.6(RINT1):c.840-5G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0321 in 1,613,462 control chromosomes in the GnomAD database, including 1,149 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (115 hom., cov: 32)
  • Exomes 𝑓: 0.033 (1034 hom.)
• Consequence: RINT1 NM_021930.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004732
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.588

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 7-105548549-G-A is Benign according to our data. Variant chr7-105548549-G-A is described in ClinVar as [Benign]. Clinvar id is 416378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-105548549-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0264 (4011/152166) while in subpopulation NFE AF= 0.0381 (2594/67998). AF 95% confidence interval is 0.0369. There are 115 homozygotes in gnomad4. There are 1992 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 115 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RINT1	NM_021930.6	c.840-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000257700.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RINT1	ENST00000257700.7	c.840-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_021930.6	P1
RINT1	ENST00000497979.5	c.*445-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4011 AN: 152048 Hom.: 115 Cov.: 32

Gnomad AFR AF: 0.00654

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.00944

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0805

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0381

Gnomad OTH AF: 0.0168

GnomAD3 exomes AF: 0.0264 AC: 6645 AN: 251414 Hom.: 171 AF XY: 0.0261 AC XY: 3551 AN XY: 135878

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.00610

Gnomad ASJ exome AF: 0.00754

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.0804

Gnomad NFE exome AF: 0.0377

Gnomad OTH exome AF: 0.0274

GnomAD4 exome AF: 0.0327 AC: 47835 AN: 1461296 Hom.: 1034 Cov.: 31 AF XY: 0.0319 AC XY: 23203 AN XY: 726964

Gnomad4 AFR exome AF: 0.00454

Gnomad4 AMR exome AF: 0.00695

Gnomad4 ASJ exome AF: 0.00796

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00310

Gnomad4 FIN exome AF: 0.0847

Gnomad4 NFE exome AF: 0.0364

Gnomad4 OTH exome AF: 0.0296

GnomAD4 genome AF: 0.0264 AC: 4011 AN: 152166 Hom.: 115 Cov.: 32 AF XY: 0.0268 AC XY: 1992 AN XY: 74374

Gnomad4 AFR AF: 0.00653

Gnomad4 AMR AF: 0.00943

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0805

Gnomad4 NFE AF: 0.0381

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0318 Hom.: 56

Bravo AF: 0.0206

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0291

EpiControl AF: 0.0289

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

RINT1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 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	-0.36
Cadd	Benign	11
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00047
dbscSNV1_RF	Benign	0.062
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: rs113947297; hg19: chr7-105188996;