NM_021930.6:c.840-5G>A

Variant names:

• chr7-105548549-G-A
• rs113947297
• NM_021930.6:c.840-5G>A

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.0004732
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.588
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• infantile liver failure syndrome 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• infantile liver failure syndrome 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 416378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 115 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RINT1	NM_021930.6	c.840-5G>A		splice_region_variant, intron_variant	Intron 6 of 14	ENST00000257700.7	NP_068749.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RINT1	ENST00000257700.7	c.840-5G>A		splice_region_variant, intron_variant	Intron 6 of 14	1	NM_021930.6	ENSP00000257700.2
RINT1	ENST00000497979.5	n.*445-5G>A		splice_region_variant, intron_variant	Intron 6 of 14	5		ENSP00000420582.1

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

GnomAD2 exomes AF: 0.0264 AC: 6645 AN: 251414 AF XY: 0.0261

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 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

African (AFR) AF: 0.00454 AC: 152 AN: 33470

American (AMR) AF: 0.00695 AC: 311 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00796 AC: 208 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00310 AC: 267 AN: 86256

European-Finnish (FIN) AF: 0.0847 AC: 4524 AN: 53404

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5766

European-Non Finnish (NFE) AF: 0.0364 AC: 40500 AN: 1111480

Other (OTH) AF: 0.0296 AC: 1788 AN: 60382

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

African (AFR) AF: 0.00653 AC: 271 AN: 41528

American (AMR) AF: 0.00943 AC: 144 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00894 AC: 31 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4820

European-Finnish (FIN) AF: 0.0805 AC: 852 AN: 10584

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0381 AC: 2594 AN: 67998

Other (OTH) AF: 0.0166 AC: 35 AN: 2108

Alfa AF: 0.0337 Hom.: 197

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 30, 2020

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

RINT1-related disorder Benign:1

Oct 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		0.59
Mutation Taster		=84/16	polymorphism (auto)

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

Other links and lift over

dbSNP: rs113947297; hg19: chr7-105188996;