rs140651827

Positions:

• chr7-105550083-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The NM_001346600.2(RINT1):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000987 in 1,613,208 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00072 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (31 hom.)
• Consequence: RINT1 NM_001346600.2 start_lost
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.55

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• BP6: Variant 7-105550083-T-C is Benign according to our data. Variant chr7-105550083-T-C is described in ClinVar as [Benign]. Clinvar id is 224922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000722 (110/152346) while in subpopulation SAS AF= 0.0128 (62/4828). AF 95% confidence interval is 0.0103. There are 1 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RINT1	NM_021930.6	c.1025T>C	p.Met342Thr	missense_variant	8/15	ENST00000257700.7	NP_068749.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RINT1	ENST00000257700.7	c.1025T>C	p.Met342Thr	missense_variant	8/15	1	NM_021930.6	ENSP00000257700.2
RINT1	ENST00000474123.1	n.29T>C		non_coding_transcript_exon_variant	1/4	2
RINT1	ENST00000497979.5	n.*630T>C		non_coding_transcript_exon_variant	8/15	5		ENSP00000420582.1
RINT1	ENST00000497979.5	n.*630T>C		3_prime_UTR_variant	8/15	5		ENSP00000420582.1

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152228 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00185 AC: 465 AN: 250982 Hom.: 13 AF XY: 0.00248 AC XY: 336 AN XY: 135640

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0126

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00101 AC: 1482 AN: 1460862 Hom.: 31 Cov.: 30 AF XY: 0.00142 AC XY: 1030 AN XY: 726678

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00329

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152346 Hom.: 1 Cov.: 32 AF XY: 0.000872 AC XY: 65 AN XY: 74500

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000510 Hom.: 0

Bravo AF: 0.000423

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	RINT1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 02, 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. -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The RINT1 p.M1? variant was not identified in the literature but was identified in dbSNP (ID: rs140651827) and ClinVar (classified as benign by Invitae). The variant was identified in control databases in 475 of 282394 chromosomes (13 homozygous) at a frequency of 0.001682, and was observed at the highest frequency in the South Asian population in 385 of 30490 chromosomes (12 homozygous) (freq: 0.01263) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.M1? variant results in the loss of the initiation codon which is predicted to lead to an absent protein and loss of function; however, the role of loss of function variants of the RINT1 gene in disease is currently not well-established. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

RINT1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 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
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.75
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Uncertain	0.029	D
Polyphen		0.0030	B
Vest4		0.55
MVP		0.36
MPC		0.22
ClinPred		0.025	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.097
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140651827; hg19: chr7-105190530; COSMIC: COSV57559291; COSMIC: COSV57559291;