rs139565013

Variant names:

• chr7-105546926-T-C
• rs139565013
• NM_021930.6:c.532T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-105546926-T-C
• chr7-105546926-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021930.6(RINT1):​c.532T>C​(p.Tyr178His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000394 in 1,602,278 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y178Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (3 hom.)
• Consequence: RINT1 NM_021930.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.42

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013274729).
• BP6: Variant 7-105546926-T-C is Benign according to our data. Variant chr7-105546926-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 241410.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 = 0.000414 (63/152254) while in subpopulation SAS AF = 0.00311 (15/4820). AF 95% confidence interval is 0.00192. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RINT1	NM_021930.6	c.532T>C	p.Tyr178His	missense_variant	Exon 5 of 15	ENST00000257700.7	NP_068749.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RINT1	ENST00000257700.7	c.532T>C	p.Tyr178His	missense_variant	Exon 5 of 15	1	NM_021930.6	ENSP00000257700.2

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000604 AC: 144 AN: 238418 AF XY: 0.000676

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.00141

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000436

Gnomad OTH exome AF: 0.000346

GnomAD4 exome AF: 0.000392 AC: 569 AN: 1450024 Hom.: 3 Cov.: 31 AF XY: 0.000444 AC XY: 320 AN XY: 721052

African (AFR) AF: 0.0000611 AC: 2 AN: 32736

American (AMR) AF: 0.000269 AC: 11 AN: 40880

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 22 AN: 25446

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00271 AC: 226 AN: 83440

European-Finnish (FIN) AF: 0.000188 AC: 10 AN: 53240

Middle Eastern (MID) AF: 0.00263 AC: 15 AN: 5696

European-Non Finnish (NFE) AF: 0.000226 AC: 251 AN: 1109052

Other (OTH) AF: 0.000534 AC: 32 AN: 59882

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74442

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.000393 AC: 6 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000513 Hom.: 1

Bravo AF: 0.000287

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000692 AC: 84

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000830

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RINT1 p.Y178H variant was identified in two individuals with breast cancer, as well as in one healthy control (Li_2016_PMID: 27544226; Park_2014_PMID: 25050558).  The variant was not identified in COSMIC, but it was identified in dbSNP (ID: rs139565013) and ClinVar (classified as likely benign by Invitae). The variant was identified in control databases in 155 of 269824 chromosomes (2 homozygous) at a frequency of 0.0005744 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Y178 residue is conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

not specified Benign:1

Jul 02, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.046
Sift	Benign	0.52	T
Sift4G	Benign	0.51	T
Polyphen		0.0070	B
Vest4		0.39
MVP		0.28
MPC		0.25
ClinPred		0.022	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.26
Mutation Taster		=93/7	polymorphism

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

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Other links and lift over

dbSNP: rs139565013; hg19: chr7-105187373; COSMIC: COSV105856132;