chr15-66386653-A-T

Variant names:

• chr15-66386653-A-T
• rs11631295
• NM_001398281.1:c.-12T>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001398281.1(TIPIN):​c.-12T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 176,038 control chromosomes in the GnomAD database, including 1,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1164 hom., cov: 33)
  • Exomes 𝑓: 0.12 (168 hom.)
• Consequence: TIPIN NM_001398281.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.37

Genes affected

TIPIN (HGNC:30750): (TIMELESS interacting protein) The protein encoded by this gene is part of the replisome complex, a group of proteins that support DNA replication. It binds TIM, which is involved in circadian rhythm regulation, and aids in protecting cells against DNA damage and stress. Two pseudogenes and two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

MAP2K1 (HGNC:6840): (mitogen-activated protein kinase kinase 1) The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals. As an essential component of MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-66386653-A-T is Benign according to our data. Variant chr15-66386653-A-T is described in ClinVar as [Benign]. Clinvar id is 561873.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIPIN	NM_001398281.1	c.-12T>A		5_prime_UTR_variant	Exon 1 of 8		NP_001385210.1
TIPIN	NM_001398283.1	c.-55T>A		5_prime_UTR_variant	Exon 1 of 8		NP_001385212.1
TIPIN	NM_001398285.1	c.-239T>A		5_prime_UTR_variant	Exon 1 of 7		NP_001385214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIPIN	ENST00000562124.5	c.-55T>A		5_prime_UTR_variant	Exon 1 of 8	5		ENSP00000457406.1
TIPIN	ENST00000568216.5	c.-12T>A		5_prime_UTR_variant	Exon 1 of 5	3		ENSP00000457172.1
TIPIN	ENST00000570251.1	c.-242T>A		5_prime_UTR_variant	Exon 1 of 5	3		ENSP00000458117.1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17831 AN: 152112 Hom.: 1161 Cov.: 33

Gnomad AFR AF: 0.0679

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0683

Gnomad SAS AF: 0.0802

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.118

GnomAD4 exome AF: 0.125 AC: 2970 AN: 23808 Hom.: 168 Cov.: 0 AF XY: 0.126 AC XY: 1386 AN XY: 11022

Gnomad4 AFR exome AF: 0.0534

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.0354

Gnomad4 FIN exome AF: 0.0714

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.117 AC: 17856 AN: 152230 Hom.: 1164 Cov.: 33 AF XY: 0.115 AC XY: 8575 AN XY: 74414

Gnomad4 AFR AF: 0.0679

Gnomad4 AMR AF: 0.126

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.0685

Gnomad4 SAS AF: 0.0802

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.116

Alfa AF: 0.134 Hom.: 174

Bravo AF: 0.116

Asia WGS AF: 0.0740 AC: 260 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.55

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11631295; hg19: chr15-66678991;