rs35961194

Variant names:

• chr7-105551610-T-C
• rs35961194
• NM_021930.6:c.1374T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_021930.6(RINT1):​c.1374T>C​(p.Ala458Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,609,958 control chromosomes in the GnomAD database, including 436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (32 hom., cov: 32)
  • Exomes 𝑓: 0.017 (404 hom.)
• Consequence: RINT1 NM_021930.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.31
• Publications: 4 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 7-105551610-T-C is Benign according to our data. Variant chr7-105551610-T-C is described in ClinVar as Benign. ClinVar VariationId is 224930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0965 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021930.6. 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.1374T>C	p.Ala458Ala	synonymous	Exon 10 of 15	NP_068749.3
	RINT1	NM_001346599.2		c.1140T>C	p.Ala380Ala	synonymous	Exon 10 of 15	NP_001333528.1
	RINT1	NM_001346601.2		c.450T>C	p.Ala150Ala	synonymous	Exon 10 of 15	NP_001333530.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RINT1	ENST00000257700.7	TSL:1 MANE Select	c.1374T>C	p.Ala458Ala	synonymous	Exon 10 of 15	ENSP00000257700.2	Q6NUQ1
	RINT1	ENST00000967558.1		c.1503T>C	p.Ala501Ala	synonymous	Exon 10 of 15	ENSP00000637617.1
	RINT1	ENST00000899074.1		c.1374T>C	p.Ala458Ala	synonymous	Exon 10 of 16	ENSP00000569133.1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2146 AN: 152210 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00369

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0411

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0239 AC: 5945 AN: 248530 AF XY: 0.0201

Gnomad AFR exome AF: 0.00315

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.00339

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0216

GnomAD4 exome AF: 0.0169 AC: 24638 AN: 1457630 Hom.: 404 Cov.: 30 AF XY: 0.0161 AC XY: 11671 AN XY: 725088

African (AFR) AF: 0.00309 AC: 103 AN: 33370

American (AMR) AF: 0.0990 AC: 4360 AN: 44060

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 120 AN: 26034

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39536

South Asian (SAS) AF: 0.00318 AC: 272 AN: 85500

European-Finnish (FIN) AF: 0.0103 AC: 551 AN: 53354

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5754

European-Non Finnish (NFE) AF: 0.0166 AC: 18450 AN: 1109832

Other (OTH) AF: 0.0128 AC: 769 AN: 60190

GnomAD4 genome AF: 0.0141 AC: 2148 AN: 152328 Hom.: 32 Cov.: 32 AF XY: 0.0132 AC XY: 987 AN XY: 74494

African (AFR) AF: 0.00368 AC: 153 AN: 41574

American (AMR) AF: 0.0411 AC: 629 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4830

European-Finnish (FIN) AF: 0.00951 AC: 101 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0175 AC: 1189 AN: 68030

Other (OTH) AF: 0.0156 AC: 33 AN: 2112

Alfa AF: 0.0169 Hom.: 41

Bravo AF: 0.0195

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	RINT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.75
PhyloP100		1.3
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs35961194; hg19: chr7-105192057;