rs1060503045

Positions:

• chr7-105563832-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000257700.7(RINT1):​c.1771G>C​(p.Val591Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RINT1 ENST00000257700.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.78

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RINT1	NM_021930.6	c.1771G>C	p.Val591Leu	missense_variant	12/15	ENST00000257700.7	NP_068749.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RINT1	ENST00000257700.7	c.1771G>C	p.Val591Leu	missense_variant	12/15	1	NM_021930.6	ENSP00000257700	P1
RINT1	ENST00000497979.5	c.*1376G>C		3_prime_UTR_variant, NMD_transcript_variant	12/15	5		ENSP00000420582

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461752 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727178

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

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

Mar 31, 2024

The p.V591L variant (also known as c.1771G>C), located in coding exon 12 of the RINT1 gene, results from a G to C substitution at nucleotide position 1771. The valine at codon 591 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 19, 2023

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 591 of the RINT1 protein (p.Val591Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RINT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 410786). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0083	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.67	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.24
Sift	Benign	0.10	T
Sift4G	Benign	0.26	T
Polyphen		0.33	B
Vest4		0.34
MutPred		0.78		Loss of catalytic residue at V591 (P = 0.0399);
MVP		0.47
MPC		0.29
ClinPred		0.89	D
GERP RS		6.2
Varity_R		0.37
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1060503045; hg19: chr7-105204279;