chr7-105536589-T-C

Variant names:

• chr7-105536589-T-C
• rs775736541
• NM_021930.6:c.113T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001346601.2(RINT1):​c.-810T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,601,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RINT1 NM_001346601.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.103
• Publications: 0 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• infantile liver failure syndrome 2

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03973949).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346601.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RINT1	NM_021930.6	MANE Select	c.113T>C	p.Ile38Thr	missense	Exon 3 of 15	NP_068749.3
	RINT1	NM_001346601.2		c.-810T>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 15	NP_001333530.1
	RINT1	NM_001346600.2		c.-907T>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 15	NP_001333529.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RINT1	ENST00000257700.7	TSL:1 MANE Select	c.113T>C	p.Ile38Thr	missense	Exon 3 of 15	ENSP00000257700.2	Q6NUQ1
	RINT1	ENST00000967558.1		c.242T>C	p.Ile81Thr	missense	Exon 3 of 15	ENSP00000637617.1
	RINT1	ENST00000899074.1		c.113T>C	p.Ile38Thr	missense	Exon 3 of 16	ENSP00000569133.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 4 AN: 244404 AF XY: 0.0000227

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 20 AN: 1449554 Hom.: 0 Cov.: 28 AF XY: 0.0000166 AC XY: 12 AN XY: 721054

African (AFR) AF: 0.00 AC: 0 AN: 32944

American (AMR) AF: 0.0000236 AC: 1 AN: 42288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25738

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39550

South Asian (SAS) AF: 0.0000239 AC: 2 AN: 83742

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000994 AC: 11 AN: 1106482

Other (OTH) AF: 0.00 AC: 0 AN: 59880

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.4
DANN	Benign	0.48
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.20	N
PhyloP100		0.10
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.0090
Sift	Benign	0.21	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.090
MVP		0.13
MPC		0.25
ClinPred		0.012	T
GERP RS		-0.34
Varity_R		0.023
gMVP		0.081
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs775736541; hg19: chr7-105177036; COSMIC: COSV57560100;