chr7-105548580-A-T

Variant names:

• chr7-105548580-A-T
• rs747465384
• NM_021930.6:c.866A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021930.6(RINT1):​c.866A>T​(p.Gln289Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q289P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RINT1 NM_021930.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.43
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10459119).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RINT1	NM_021930.6	MANE Select	c.866A>T	p.Gln289Leu	missense	Exon 7 of 15	NP_068749.3
	RINT1	NM_001346599.2		c.632A>T	p.Gln211Leu	missense	Exon 7 of 15	NP_001333528.1
	RINT1	NM_001346601.2		c.-59A>T		5_prime_UTR	Exon 7 of 15	NP_001333530.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RINT1	ENST00000257700.7	TSL:1 MANE Select	c.866A>T	p.Gln289Leu	missense	Exon 7 of 15	ENSP00000257700.2
	RINT1	ENST00000967558.1		c.995A>T	p.Gln332Leu	missense	Exon 7 of 15	ENSP00000637617.1
	RINT1	ENST00000899074.1		c.866A>T	p.Gln289Leu	missense	Exon 7 of 16	ENSP00000569133.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.026
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.4
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.029
Sift	Benign	0.24	T
Sift4G	Uncertain	0.035	D
Polyphen		0.26	B
Vest4		0.32
MutPred		0.36		Loss of solvent accessibility (P = 0.0128)
MVP		0.32
MPC		0.19
ClinPred		0.76	D
GERP RS		4.6
Varity_R		0.084
gMVP		0.30
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs747465384; hg19: chr7-105189027;