15-66386653-A-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 publications found

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]

MAP2K1 Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• cardiofaciocutaneous syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, ClinGen
• Noonan syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001398281.1. 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
	TIPIN	NM_001398281.1		c.-12T>A		5_prime_UTR	Exon 1 of 8	NP_001385210.1	Q9BVW5
	TIPIN	NM_001398283.1		c.-55T>A		5_prime_UTR	Exon 1 of 8	NP_001385212.1	Q9BVW5
	TIPIN	NM_001398285.1		c.-239T>A		5_prime_UTR	Exon 1 of 7	NP_001385214.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIPIN	ENST00000912702.1		c.-30T>A		5_prime_UTR	Exon 1 of 8	ENSP00000582761.1
	TIPIN	ENST00000912703.1		c.-12T>A		5_prime_UTR	Exon 1 of 8	ENSP00000582762.1
	TIPIN	ENST00000955702.1		c.-107T>A		5_prime_UTR	Exon 1 of 9	ENSP00000625761.1

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

African (AFR) AF: 0.0534 AC: 39 AN: 730

American (AMR) AF: 0.128 AC: 65 AN: 506

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 193 AN: 1536

East Asian (EAS) AF: 0.101 AC: 528 AN: 5204

South Asian (SAS) AF: 0.0354 AC: 7 AN: 198

European-Finnish (FIN) AF: 0.0714 AC: 1 AN: 14

Middle Eastern (MID) AF: 0.130 AC: 20 AN: 154

European-Non Finnish (NFE) AF: 0.139 AC: 1886 AN: 13542

Other (OTH) AF: 0.120 AC: 231 AN: 1924

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

African (AFR) AF: 0.0679 AC: 2822 AN: 41546

American (AMR) AF: 0.126 AC: 1929 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3472

East Asian (EAS) AF: 0.0685 AC: 354 AN: 5170

South Asian (SAS) AF: 0.0802 AC: 387 AN: 4824

European-Finnish (FIN) AF: 0.147 AC: 1558 AN: 10588

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 9994 AN: 68018

Other (OTH) AF: 0.116 AC: 246 AN: 2114

Alfa AF: 0.134 Hom.: 174

Bravo AF: 0.116

Asia WGS AF: 0.0740 AC: 260 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.55
PhyloP100		-3.4
PromoterAI		-0.038	Neutral

Splicing

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

Other links and lift over

dbSNP: rs11631295; hg19: chr15-66678991;