dbSNP rs112914598: RINT1:c.2067+6T>A (chr7-105565463-T-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_021930.6(RINT1):c.2067+6T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,613,114 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 7 hom., cov: 33)

Exomes 𝑓: 0.011 ( 115 hom. )

Consequence

RINT1
NM_021930.6 splice_region, intron

Scores

Splicing: ADA: 0.2430

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0190

Publications

3 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 links:

EFCAB10 (HGNC:34531): (EF-hand calcium binding domain 10) Predicted to enable calcium ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

EFCAB10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 7-105565463-T-A is Benign according to our data. Variant chr7-105565463-T-A is described in ClinVar as Benign. ClinVar VariationId is 241403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00706 (1075/152330) while in subpopulation NFE AF = 0.0123 (837/68034). AF 95% confidence interval is 0.0116. There are 7 homozygotes in GnomAd4. There are 489 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RINT1	NM_021930.6	MANE Select	c.2067+6T>A	splice_region intron	N/A	NP_068749.3
EFCAB10	NM_001355526.2	MANE Select	c.384-16A>T	intron	N/A	NP_001342455.1
EFCAB10	NM_001355530.2		c.*86A>T	3_prime_UTR	Exon 5 of 5	NP_001342459.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RINT1	ENST00000257700.7	TSL:1 MANE Select	c.2067+6T>A	splice_region intron	N/A	ENSP00000257700.2
EFCAB10	ENST00000480514.6	TSL:1 MANE Select	c.384-16A>T	intron	N/A	ENSP00000418678.1
EFCAB10	ENST00000485614.5	TSL:5	c.*86A>T	3_prime_UTR	Exon 5 of 5	ENSP00000417841.1

Frequencies

GnomAD3 genomes

AF:

0.00706

AC:

1075

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00452

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00659

AC:

1656

AN:

251124

AF XY:

0.00643

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.00400

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00499

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.00638

GnomAD4 exome

AF:

0.0106

AC:

15480

AN:

1460784

Hom.:

115

Cov.:

AF XY:

0.0102

AC XY:

7426

AN XY:

726616

show subpopulations

African (AFR)

AF:

0.00179

AC:

AN:

33438

American (AMR)

AF:

0.00421

AC:

188

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.000919

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00175

AC:

151

AN:

86232

European-Finnish (FIN)

AF:

0.00638

AC:

341

AN:

53410

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0128

AC:

14267

AN:

1111108

Other (OTH)

AF:

0.00734

AC:

443

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

794

1588

2382

3176

3970

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

526

1052

1578

2104

2630

<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

AF:

0.00706

AC:

1075

AN:

152330

Hom.:

Cov.:

AF XY:

0.00656

AC XY:

489

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

41572

American (AMR)

AF:

0.00536

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00452

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0123

AC:

837

AN:

68034

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

119

178

238

297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00977

Hom.:

Bravo

AF:

0.00704

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0116

EpiControl

AF:

0.0104

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

RINT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.019

BranchPoint Hunter

2.0

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.24

dbscSNV1_RF

Benign

0.41

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over