rs35531972

chr7-105565368-C-Achr7-105565368-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021930.6(RINT1):c.1978C>A(p.Leu660Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,614,154 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L660F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (8 hom., cov: 33)
  • Exomes 𝑓: 0.014 (178 hom.)
• Consequence: RINT1 NM_021930.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.18

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]

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008720905).
• BP6: Variant 7-105565368-C-A is Benign according to our data. Variant chr7-105565368-C-A is described in ClinVar as [Benign]. Clinvar id is 224933.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 = 0.0106 (1611/152318) while in subpopulation NFE AF= 0.0166 (1128/68034). AF 95% confidence interval is 0.0158. There are 8 homozygotes in gnomad4. There are 758 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RINT1	NM_021930.6	c.1978C>A	p.Leu660Ile	missense_variant	13/15	ENST00000257700.7
EFCAB10	NM_001355526.2	c.*79G>T		3_prime_UTR_variant	5/5	ENST00000480514.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RINT1	ENST00000257700.7	c.1978C>A	p.Leu660Ile	missense_variant	13/15	1	NM_021930.6	P1
EFCAB10	ENST00000480514.6	c.*79G>T		3_prime_UTR_variant	5/5	1	NM_001355526.2	A2

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1613 AN: 152200 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.00669

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0117 AC: 2951 AN: 251436 Hom.: 32 AF XY: 0.0118 AC XY: 1605 AN XY: 135888

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00862

Gnomad ASJ exome AF: 0.0362

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00320

Gnomad FIN exome AF: 0.00679

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0136 AC: 19881 AN: 1461836 Hom.: 178 Cov.: 31 AF XY: 0.0134 AC XY: 9738 AN XY: 727218

Gnomad4 AFR exome AF: 0.00332

Gnomad4 AMR exome AF: 0.00798

Gnomad4 ASJ exome AF: 0.0348

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00311

Gnomad4 FIN exome AF: 0.00693

Gnomad4 NFE exome AF: 0.0152

Gnomad4 OTH exome AF: 0.0131

GnomAD4 genome AF: 0.0106 AC: 1611 AN: 152318 Hom.: 8 Cov.: 33 AF XY: 0.0102 AC XY: 758 AN XY: 74484

Gnomad4 AFR AF: 0.00272

Gnomad4 AMR AF: 0.00727

Gnomad4 ASJ AF: 0.0372

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00669

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0170 Hom.: 47

Bravo AF: 0.0108

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0171 AC: 147

ExAC AF: 0.0115 AC: 1396

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.0207

EpiControl AF: 0.0197

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2020

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

RINT1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.16
Sift	Benign	0.33	T
Sift4G	Benign	0.24	T
Polyphen		1.0	D
Vest4		0.23
MPC		0.76
ClinPred		0.011	T
GERP RS		5.5
Varity_R		0.26
gMVP		0.17

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

LitVar

Other links and lift over

dbSNP: rs35531972; hg19: chr7-105205815;