7-105532341-C-T

Variant names:

• chr7-105532341-C-T
• rs764326516
• NM_021930.6:c.26C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021930.6(RINT1):​c.26C>T​(p.Ala9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A9S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RINT1 NM_021930.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.417
• Publications: 0 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: 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

ENSG00000295934 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.065345824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RINT1	NM_021930.6	c.26C>T	p.Ala9Val	missense_variant	Exon 1 of 15	ENST00000257700.7	NP_068749.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RINT1	ENST00000257700.7	c.26C>T	p.Ala9Val	missense_variant	Exon 1 of 15	1	NM_021930.6	ENSP00000257700.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000911 AC: 2 AN: 219496 AF XY: 0.00000828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447418 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719248

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

African (AFR) AF: 0.00 AC: 0 AN: 33228

American (AMR) AF: 0.0000231 AC: 1 AN: 43244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.00 AC: 0 AN: 39124

South Asian (SAS) AF: 0.00 AC: 0 AN: 84034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1106946

Other (OTH) AF: 0.00 AC: 0 AN: 59858

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000830 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A9V variant (also known as c.26C>T), located in coding exon 1 of the RINT1 gene, results from a C to T substitution at nucleotide position 26. The alanine at codon 9 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.3
DANN	Uncertain	0.98
DEOGEN2	Benign	0.038	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		0.42
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.16	N;N
REVEL	Benign	0.069
Sift	Benign	0.061	T;D
Sift4G	Benign	0.062	T;T
Polyphen		0.0	B;.
Vest4		0.14
MutPred		0.15		Loss of glycosylation at S10 (P = 0.167);Loss of glycosylation at S10 (P = 0.167);
MVP		0.34
MPC		0.19
ClinPred		0.044	T
GERP RS		2.5
PromoterAI		-0.0050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.13
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs764326516; hg19: chr7-105172788;