7-105551578-CA-CAA

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_021930.6(RINT1):c.1348dupA(p.Met450AsnfsTer16) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RINT1
NM_021930.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.15

Publications

0 publications found

Variant links:

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

RINT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-105551578-C-CA is Pathogenic according to our data. Variant chr7-105551578-C-CA is described in ClinVar as Pathogenic. ClinVar VariationId is 410783.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RINT1	NM_021930.6 link	c.1348dupA	p.Met450AsnfsTer16	frameshift_variant	Exon 10 of 15	ENST00000257700.7	NP_068749.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RINT1	ENST00000257700.7 link	c.1348dupA	p.Met450AsnfsTer16	frameshift_variant	Exon 10 of 15	1	NM_021930.6	ENSP00000257700.2
RINT1	ENST00000474123.1 link	n.352dupA		non_coding_transcript_exon_variant	Exon 3 of 4	2
RINT1	ENST00000497979.5 link	n.*953dupA		non_coding_transcript_exon_variant	Exon 10 of 15	5		ENSP00000420582.1
RINT1	ENST00000497979.5 link	n.*953dupA		3_prime_UTR_variant	Exon 10 of 15	5		ENSP00000420582.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718344

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32852

American (AMR)

AF:

0.00

AC:

AN:

41772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25628

East Asian (EAS)

AF:

0.00

AC:

AN:

39204

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103896

Other (OTH)

AF:

0.00

AC:

AN:

59654

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Sep 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Met450Asnfs*16) in the RINT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RINT1 are known to be pathogenic (PMID: 31204009). 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: 410783). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.2

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over