chr7-105565314-A-T

Position:

• chr7-105565314-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021930.6(RINT1):​c.1924A>T​(p.Met642Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RINT1 NM_021930.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16590005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RINT1	NM_021930.6	c.1924A>T	p.Met642Leu	missense_variant	13/15	ENST00000257700.7	NP_068749.3
EFCAB10	NM_001355526.2	c.*133T>A		3_prime_UTR_variant	5/5	ENST00000480514.6	NP_001342455.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RINT1	ENST00000257700.7	c.1924A>T	p.Met642Leu	missense_variant	13/15	1	NM_021930.6	ENSP00000257700	P1
EFCAB10	ENST00000480514.6	c.*133T>A		3_prime_UTR_variant	5/5	1	NM_001355526.2	ENSP00000418678	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 27, 2016

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RINT1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This sequence change replaces methionine with leucine at codon 642 of the RINT1 protein (p.Met642Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.072
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.70	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	0.49	T
Polyphen		0.0010	B
Vest4		0.47
MutPred		0.50		Gain of sheet (P = 0.0827);
MVP		0.20
MPC		0.18
ClinPred		0.70	D
GERP RS		4.3
Varity_R		0.17
gMVP		0.31

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: rs1060503044; hg19: chr7-105205761;