rs112914598

Positions:

• chr7-105565463-T-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_021930.6(RINT1):​c.2067+6T>A variant causes a splice donor 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. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0071 (7 hom., cov: 33)
  • Exomes 𝑓: 0.011 (115 hom.)
• Consequence: RINT1 NM_021930.6 splice_donor_region, intron
• Scores: Splicing: ADA: 0.2430
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0190

Genes affected

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

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

Verdict is Benign. Variant got -18 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 2 / 10). 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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFCAB10	NM_001355526.2	c.*-16A>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000480514.6
RINT1	NM_021930.6	c.2067+6T>A		splice_donor_region_variant, intron_variant		ENST00000257700.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RINT1	ENST00000257700.7	c.2067+6T>A		splice_donor_region_variant, intron_variant		1	NM_021930.6	P1
EFCAB10	ENST00000480514.6	c.*-16A>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001355526.2	A2

Frequencies

GnomAD3 genomes AF: 0.00706 AC: 1075 AN: 152212 Hom.: 7 Cov.: 33

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

GnomAD3 exomes AF: 0.00659 AC: 1656 AN: 251124 Hom.: 7 AF XY: 0.00643 AC XY: 873 AN XY: 135746

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 SAS exome AF: 0.00173

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.: 31 AF XY: 0.0102 AC XY: 7426 AN XY: 726616

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00421

Gnomad4 ASJ exome AF: 0.000919

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00175

Gnomad4 FIN exome AF: 0.00638

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.00734

GnomAD4 genome AF: 0.00706 AC: 1075 AN: 152330 Hom.: 7 Cov.: 33 AF XY: 0.00656 AC XY: 489 AN XY: 74496

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00977 Hom.: 2

Bravo AF: 0.00704

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0104

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	EFCAB10: BS1, BS2; RINT1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

RINT1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.88
BranchPoint Hunter		2.0

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

LitVar

Other links and lift over

dbSNP: rs112914598; hg19: chr7-105205910;